Substituted Azepine Derivatives As Serotonin Receptor Modulators

ABSTRACT

The present invention generally relates to compounds and pharmaceutical compositions containing the compounds. More specifically, compounds of the present invention are hexahydroazepinoindole and octahydroazepinoindole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/170,266, filed Jun. 29, 2005, the disclosure of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention generally relates to a series of compounds, topharmaceutical compositions containing the compounds, and to use of thecompounds and compositions as therapeutic agents. More specifically,compounds of the present invention are hexahydrothienoazepine andoctahydrothienoazepine compounds. These compounds are serotonin receptor(5-HT) ligands and are useful for treating diseases, disorders, andconditions wherein modulation of the activity of serotonin receptors(5-HT) is desired (e.g. addiction, anxiety, depression and obesity).

BACKGROUND OF THE INVENTION

Serotonin has been implicated in a number of diseases, disorders, andconditions that originate in the central nervous system, includingdiseases, disorders, and conditions related to, for example, sleeping,eating, perceiving pain, controlling body temperature, controlling bloodpressure, depression, anxiety, addiction and schizophrenia. Serotoninalso plays an important role in peripheral systems, such as thegastrointestinal system, where it has been found to mediate a variety ofcontractile, secretory, and electrophysiologic effects.

Because of the broad distribution of serotonin within the body, there isa need for drugs that affect serotonergic systems. In particular,agonists, partial agonists, and antagonists of serotonergic systems areof interest for the treatment of a wide range of disorders, includinganxiety, depression, hypertension, migraine, obesity, compulsivedisorders, schizophrenia, autism, neurodegenerative disorders (e.g.,Alzheimer's disease, Parkinsonism, and Huntington's chorea), andchemotherapy-induced vomiting.

The major classes of serotonin receptors (5-HT-₁ _(—) ₇) contain one toseven separate receptors that have been formally classified. SeeGlennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; andD. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203.

For example, the 5-HT₂ family of receptors contains 5-HT_(2a),5-HT_(2b), and 5-HT_(2c) subtypes, which have been grouped together onthe basis of primary structure, secondary messenger system, andoperational profile. All three 5-HT₂ subtypes are G-protein coupled,activate phospholipase C as a principal transduction mechanism, andcontain a seven-transmembrane domain structure. There are distinctdifferences in the distribution of the three 5-HT₂ subtypes in a mammal.The 5-HT_(2b) and 5-HT_(2a) receptors are widely distributed in theperipheral nervous system, with 5-HT_(2a) also found in the brain. The5-HT_(2c) receptor has been found only in the central nervous system,being highly expressed in many regions of the human brain. See G.Baxter, et al. Trends in Pharmacol. Sci. 1995, 16, 105-110.

Subtype 5-HT_(2a) has been associated with effects includingvasoconstriction, platelet aggregation, and bronchoconstriction, as wellas certain CNS effects, while subtype 5-HT_(2c) has been associated withdiseases that include depression, anxiety, obsessive compulsivedisorder, addiction, panic disorders, phobias, psychiatric syndromes,and obesity. Very little is known about the pharmocologic role of the5-HT_(2b) receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs,1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769;J. R. Martin, et al., The Journal of Pharmacology and ExperimentalTherapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., 1. Med, Chem.,1998, 41, 1598-1612; G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A.Dekeyne, et al., Neuropharmacology, 1999, 38, 415-423.

WO 93/13105 discloses thiophene derivatives; U.S. Pat. No. 4,414,225discloses thiophene, furan and pyrrole derivatives and WO 96/12201discloses furan derivatives.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula

where X is S, O or NR₅;R₁ and R₂ are independently selected from the group consisting of H,halogen, C₁₋₈ alkyl,C₁₋₈ alkylaryl, C₁₋₈ alkyl heteroaryl, C₂₋₈ alkenyl, perhalo alkyl, CN,OR₅, SR₅, N(R₅)₂, CON(R₅)₂, NR₅COR₅, NR₅CO₂R₅, SO₂N(R₅)₂, NR₅SO₂R₅, aryland heteroaryl, wherein said aryl or heteroaryl can be optionallysubstituted with up to three substituents selected from alkyl, halogenand alkoxy;R₃ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₅alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂, and aryl;R_(3a) is H or R₃ and R_(3a) taken together are —CH₂CH₂— orR₂ and R₃ form a 5- or 6-member ring;R₄ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂, and aryl;R_(4a) is H or R₄ and R_(4a) taken together are —CH₂CH₂—;R₅ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl;with the provisos that at least one of R₁, R₂, R₃, R_(3a), R₄, andR_(4a) must be other than hydrogen;if R₃ is OH, then at least one of R₁, R₂, R₄, and R_(4a) must be otherthan hydrogen; andif X is O, then at least one of R₃, R_(3a), R₄, and R_(4a) must be otherthan hydrogen.

Another embodiment of the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Still another embodiment of the present invention provides a method oftreating a disease, disorder and/or condition in a mammal (e.g., animalor human), wherein a 5-HT₂, receptor is implicated and modulation of a5-HT_(2c) function is desired. The method comprises administering atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the mammal.

Yet another embodiment of the present invention comprises a method ofmodulating 5-HT receptor function with an effective amount of compoundof Formula (I), or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention provides a method oftreating or preventing diseases, disorders, and/or conditions of thecentral nervous system. The method comprises administering atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the mammal.

Specific diseases, disorders and/or conditions for which compounds ofthe Formula (I) may have activity include obesity, depression,schizophrenia, anxiety, obsessive compulsive disorder, addiction, panicdisorders, sleep disorders, migraine, Type II diabetes, epilepsy,phobias and psychiatric syndromes.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described:

As used herein, the term “alkyl” includes straight chained and branchedhydrocarbon groups containing the indicated number of carbon atoms,typically methyl, ethyl, and straight chain and branched propyl andbutyl groups. The term “alkyl” also encompasses cycloalkyl, i.e., acyclic C₃-C₈ hydrocarbon group, such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Reference to an individual group or moiety,such as “propyl,” embraces only the straight chain group or moiety. Abranched chain isomer, such as “isopropyl,” is specifically referred to.

The term “alkenyl” as used herein, alone or in combination, refers to asubstituted or unsubstituted straight-chain or substituted orunsubstituted branched-chain alkenyl radical containing from 2 to 10carbon atoms. Examples of such radicals include, but are not limited to,ethenyl. E- and Z-pentenyl, decenyl and the like.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term “alkyl” is as defined above.Examples of suitable alkyl ether radicals include, but are not limitedto, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like.

The term “halo” is defined herein to include fluoro, chloro, bromo, oriodo. Similarly, the term “halogen” is defined herein to includefluorine, chlorine, bromine, and iodine.

The term “amino”, alone or in combination, includes the group —NH₂ or—NR_(a)R_(b) wherein R_(a) and R_(b) are independently hydrogen, alkyl,alkylaryl, or aryl.

The term “aryl,” alone or in combination, is defined herein as amonocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) thatcan be unsubstituted or substituted, for example, with one or more, andin particular one to three of the following substituents selected fromthe group consisting of H, halo; CN, NO₂, CF₃, N₃, C₁₋₆alkyl, OH,NR^(a)R^(b), OC₁₋₆ alkyl, OR^(a), C(═O)NR^(a)R^(b), C(═S)NR^(a)R^(b),tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl,cyanoguanadinyl, and aryl. Generally, “aryl” denotes a phenyl group, oran ortho-fused bicyclic carbocyclic group having nine to ten ring atomsin which at least one ring is aromatic (e.g. naphthyl ortetrahydronaphthyl). The term “aryl” also is abbreviated in the variouschemical structures as “Ar.”

The term “heteroaryl” is defined herein as a monocyclic, bicyclic, ortricyclic ring system containing one, two, or three aromatic rings andcontaining at least one nitrogen, oxygen, or sulfur atom in an aromaticring, and which can be unsubstituted or substituted, for example, withone or more, and in particular one to three, substituents, like halo,alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro,amino, alkylamino, acylamino, alkylthio, alkylsulfonyl, andalkylsulfonyl. Examples of heteroaryl groups include, but are notlimited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nH-carbazolyl,acridinyl, benzo[b]thienyl, benzothiazolyl, 13-carbolinyl, carbazolyl,chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl,imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl,phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, andxanthenyl. In one embodiment the term “heteroaryl” denotes a monocyclicaromatic ring containing five or six ring atoms containing carbon and 1,2, 3, or 4 heteroatoms independently selected from the group consistingof non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O,C₁ _(—) ₄alkyl, phenyl or benzyl. In another embodiment heteroaryldenotes an ortho-fused bicyclic heterocycle of about eight to ten ringatoms derived therefrom, particularly a benz-derivative or one derivedby fusing a propylene, or tetramethylene diradical thereto.

The term “Het” generally represents a heterocyclic group, saturated orpartially unsaturated, containing at least one heteroatom selected fromthe group consisting of oxygen, nitrogen, and sulfur, and optionallysubstituted with C₁₋₆alkyl or C(═O)OR⁶. Typically “Het” is a monocyclic,bicyclic, or tricyclic group containing one or more heteroatoms selectedfrom the group consisting of oxygen, nitrogen, and sulfur. A “Het” groupalso can contain an oxo group (═O) attached to the ring. Nonlimitingexamples of Het groups include 1,3-dihydrobenzofuran, 1,3-dioxolane,1,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl,imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl,morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine,pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, andthiomorpholine.

Preferred embodiments of the present invention include:

Embodiment 1

R₁ and R₂ are independently selected from the group consisting of H,halogen, C₁₋₈ alkyl,C₁₋₈ alkylaryl, C₁₋₈ alkyl heteroaryl, C₂₋₈ alkenyl, perhalo alkyl, CN,OR₅, SR₅, N(R₅)₂, CON(R₅)₂, NR₅COR₅, NR₅CO₂R₅, SO₂N(R₅)₂, NR₅SO₂R₅, aryland heteroaryl, wherein said aryl or heteroaryl can be optionallysubstituted with up to three substituents selected from alkyl, halogenand alkoxy;R₃ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂, and aryl;R_(3a) is H or R₃ and R_(3a) taken together are CH₂CH₂— orR₂ and R₃ form a 5- or 6-member ring;R₄ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂ and aryl;R_(4a) is H or R₄ and R_(4a) taken together are —CH₂CH₂—;R₅ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl;with the provisos that at least one of R₁, R₂, R₃, R_(3a), R₄, andR_(4a) must be other than hydrogen; and if R₃ is OH, then at least oneof R₁, R₂, R₄, and R_(4a) must be other than hydrogen.

Embodiment 2

R₁ and R₂ are independently selected from the group consisting of H,halogen, C₁₋₈ alkyl,

C₁₋₈ alkylaryl, C₁₋₈ alkyl heteroaryl, C₂₋₈ alkenyl, perhalo alkyl, CN,OR₅, SR₅, N(R₅)₂, CON(R₅)₂, NR₅COR₅, NR₅CO₂R₅, SO₂N(R₅)₂, NR₅SO₂R₅, aryland heteroaryl, wherein said aryl or heteroaryl can be optionallysubstituted with up to three substituents selected from alkyl, halogenand alkoxy;R₃ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂, and aryl;R_(3a) is H or R₃ and R_(3a) taken together are —CH₂CH₂— orR₂ and R₃ form a 5- or 6-member ring;R₄ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂ and aryl;R_(4a) is H or R₄ and R_(4a) taken together are —CH₂CH₂—;R₅ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl;with the provisos that at least one of R₁, R₂, R₃, R_(3a), R₄, andR_(4a) must be other than hydrogen; at least one of R₃, R_(3a), R₄, andR_(4a) must be other than hydrogen; and if R₃ is OH, then at least oneof R₁, R₂, R₄, and R_(4a) must be other than hydrogen.

Embodiment 3

R₁ and R₂ are independently selected from the group consisting of H,halogen, C₁₋₈ alkyl, C₁₋₈ alkylaryl, C₁₋₈ alkyl heteroaryl, C₂₋₈alkenyl, perhalo alkyl, CN, OR₅, SR₅, N(R₅)₂, CON(R₅)₂, NR₅COR₅,NR₅CO₂R₅, SO₂N(R₅)₂, NR₅SO₂R₅, aryl and heteroaryl, wherein said aryl orheteroaryl can be optionally substituted with up to three substituentsselected from alkyl, halogen and alkoxy;

R₃ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂, and aryl;R_(3a) is H or R₃ and R_(3a) taken together are —CH₂CH₂— orR₂ and R₃ form a 5- or 6-member ring;R₄ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH,—COO—C₁₋₈ alkyl, —CON(R₅)₂, and aryl;R_(4a) is H or R₄ and R_(4a) taken together are ±CH₂CH₂—;R₅ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylaryl, C₁₋₈ alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl;with the provisos that at least one of R₁, R₂, R₃, R_(3a), R₄, andR_(4a) must be other than hydrogen; and if R₃ is OH, then at least oneof R₁, R₂, R₄, and R_(4a) must be other than hydrogen.

Preferably X is S;

R₁ is selected from the group consisting of halogen, C₁₋₈ alkyl, OR₅,SO₂N(R₅)₂ and perhaloalkyl;

R₂ is selected from the group consisting of hydrogen, halogen, C₁₋₈alkyl and OR₅, or together with R₃ forms a 5-membered ring;

R₃ is hydrogen or C₁₋₈ alkyl;

R₃ is hydrogen;

R₄ is hydrogen or C₁₋₈ alkyl;

R₄ is hydrogen; and

R₅ is hydrogen or, C₁₋₈ alkyl or, together with the atom to which it isattached form a heteroaryl ring.

Presently preferred compounds include

-   2-Bromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2,3-Dibromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2,3-Dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Chloro-4-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Chloro-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2,3-Dichloro-4-methyl-5,6,7,8-tetrahydro-thieno[2,3-d]azepine;-   2-(4-Trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(3-Trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(2-Trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(2,5-Difluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(3-Chloro-4-fluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(2,5-Dichloro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(5-Fluoro-2-methoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine,-   2-(3,4,5-Trimethoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(4-Ethoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(4-Ethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(3-Methoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(3-Fluoro-biphenyl-4-yl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(2-Fluoro-biphenyl-4-yl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine,-   2-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-8-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(Pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic acid    dimethylamide;-   3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic acid    dimethylamide;-   2-Bromo-4,4a,5,6,7,8-hexadydro-3H-1-thia-6-aza-cyclopenta[cd]azulene;-   2-Methyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene;-   2-Trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   3-Bromo-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-tert-Butyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3]d]azepine;-   2-Naphthalene-1-yl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Naphthalene-2-yl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(2,6-Difluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   3-(2,6-Difluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(2-Chloro-6-fluoro-benzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine,-   3-Bromo-2-(2-chloro-6-fluoro-benzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-cd]azepine;-   2-Amino-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-3-carboxylic acid    ethyl ester;-   2-Amino-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxylic acid    ethyl ester;-   5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-3-carboxylic acid ethyl    ester; and-   5,6,7,8-Tetrahydro-4H-thieno[2,3-c]azepine-3-carboxylic acid ethyl    ester.

Particularly preferred compounds include:

-   2,3-Dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-Bromo-8-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   2-(Pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic acid    dimethylamide;-   3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic acid    dimethylamide;-   2-Bromo-4,4a,5,6,7,8-hexadydro-3H-1-thia-6-aza-cyclopenta[cd]azulene;-   2-Methyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene;-   2-Trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;-   3-Bromo-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;    and-   2-tert-Butyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3]d]azepine.

Certain compounds of the invention may exist in different isomeric (e.g.enantiomers and distereoisomers) forms. The invention contemplates allsuch isomers both in pure form and in admixture, including racemicmixtures. Enol forms are also included.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, e.g., hemi-hydrate. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water, ethanol, and the like are equivalent to the unsolvatedforms for the purposes of the invention.

Certain compounds of the invention also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the nitrogen atoms mayform salts with acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, furmaric, succinic, ascorbic, maleic, methanesulfonicand other mineral carboxylic acids well known to those in the art. Thesalts are prepared by contacting the free base form with a sufficientamount of the desired acid to produce a salt in the conventional manner.The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous hydroxidepotassium carbonate, ammonia, and sodium bicarbonate. The free baseforms differ from their respective salt forms somewhat in certainphysical properties, such as solubility in polar solvents, but the acidsalts are equivalent to their respective free base forms for purposes ofthe invention. (See, for example S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein byreference.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients. The phrase “therapeutically effective amount” of thecompound of the invention means a sufficient amount of the compound totreat disorders, at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgement. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0001 to about 1000mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.001 to about 5 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

The compositions can also be delivered through a catheter for localdelivery at a target site, via an intracoronary stent (a tubular devicecomposed of a fine wire mesh), or via a biodegradable polymer. Thecompounds may also be complexed to ligands, such as antibodies, fortargeted delivery.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pillsand granules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfumingagents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. Prodrugs of the present invention may be rapidlytransformed in vivo to the parent compound of the above formula, forexample, by hydrolysis in blood. A thorough discussion is provided in T.Higuchi and V. Stella, Pro-druqs as Novel Delivery Systems, V. 14 of theA.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press (1987), hereby incorporated by reference.

The compounds of the present invention may be prepared by the proceduresset forth in Schemes. The general analytical conditions set forth wereutilized in all examples.

General Analytical Conditions:

HPLC analysis and purification was performed using a Waters 2525 binarygradient pump, Waters 2767 sample manager, Waters 2487 UV detector (220and 254 nM), and Waters Micromass ZQ electrospray mass spec detector.The Micromass ZQ was set for both positive and negative ionization (conevoltage=25 and 50, respectively). Analytical HPLC analysis was performedas follows:

Waters XTerra MS 018 50×4.6 mm 3.5 μm columnMobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and AcetonitrileAcetonitrile: 10 to 75% at 3.5 minutes, 75 to 99% at 3.9 minutes, 99%hold to 4.2 minutes, 99 to 10% at 4.5 minutes, re-equilibrate.

Preparative HPLC was performed as follows:

Waters XTerra Prep MS 018 50×19 mm 5 μm columnMobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and AcetonitrileAcetonitrile: 10 to 99% at 8 minutes, 99% hold to 9 minutes, 99 to 10%at 9.5 minutes, re-equilibrateNMR analysis was performed using a Bruker BioSpin UltraShield NMR (300MHz)

Example 1 2-Bromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme 1a)

a.) [Ethoxycarbonyl-(2-thiophen-2-yl-ethyl)-amino]-acetic acid ethylester

2-Thiophen-2-yl-ethylamine (21 g, 165 mmol) was stirred in 1 liter ofDCM. Ethyl glyoxylate (165 mmol, 50% in toluene) was added followed by50 uL HOAc. The reaction was stirred for 10 minutes after which timeNaBH(OAc)₃ (214 mmol, 45 g) was added slowly. After 15 minutes HOAc wasadded (214 mmol) and the reaction was stirred for 20 minutes. Thereaction was cited and the crude material was dissolved in 500 mL eachof THF and water. NaHCO₃ (42 g, 500 mmol) was added followed by ethylchloroformate (21 mL, 214 mmol). Saturated NaHCO₃ was added slowly tothe reaction until the gas evolution was minimal. After stirringovernight, the reaction was diluted with EtOAc (400 mL). The product wasextracted 2× into EtOAc, dried over MgSO₄, and concentrated to give thesubtitle product as a dark oil that was used without furtherpurification.

b.) [Ethoxycarbonyl-(2-thiophen-2-yl-ethyl)-amino]-acetic acid

The crude material from step a) (−165 mmol) was dissolved in EtOH (700mL) and treated with 600 mL of 1M NaOH. After stirring overnight, thereaction was acidified with concentrated HCl to pH˜1. The crude reactionwas diluted with EtOAc (400 mL) and washed with water. The water wasback-extracted with EtOAc. The combined organic extracts were washedwith water (2×) and dried over MgSO₄. Concentration and evaporation fromtoluene (2×) gave the subtitle product as a solid, which was usedwithout further purification.

c.) 4-Oxo-4,5,7,8-tetrahydro-thieno(2,3-diazepine-6-carboxylic acidethyl ester

The product of step b) (˜165 mmol) was dissolved in 1 L of DCM. DMF (100uL) was added followed slowly by oxalyl chloride (21.7 mL, 247 mmol).After 1 hour the reaction was concentrated to dryness and the crudematerial was re-dissolved in DCE (1 L). AlCl₃ (55 g, 410 mmol) wascarefully added and the reaction was stirred at room temperature for ½hour. The crude reaction was quenched with ice, diluted with EtOH (300mL), washed with water (3×), and dried over MgSO₄. The title product waspurified by silica gel chromatography (30% EtOAc in Hexanes) to give10.5 g of the subtitle compound as an off-white solid. MS: ESI(positive): 240 (M+H).

d.) 4,5,7,8-Tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid ethylester

AlCl₃ (3.95 g, 29.7 mmol) was added to 50 mL DCM at 0° C. Borane-t-butylamine complex (5.2 g, 59.5 mmol) was added followed by the product ofstep c) (2.37 g, 9.9 mmol) dissolved in DCM (50 mL). The reaction wasstirred for 2 hours at room temperature after which time another 3.95 g(29.7 mmol) of AlCl₃ was added. After stirring 10 minutes, the reactionwas quenched carefully with 0.1 M HCl (˜50 mL). After concentration ofthe organic solvent, the crude reaction mixture was partitioned between1M HCl and EtOAc (70 mL each). The aqueous layer was back extracted1×EtOAc. The combined organic layers were dried over MgSO₄ andconcentrated. The subtitle product (1.45 g) was obtained afterpurification by silica gel chromatography (EtOAc/Hexanes-gradient). ¹HNMR (300 MHz, CDCl₃) 6.96 (d, J=5 Hz, 1H), 6.76 (d, J=5 Hz, 1H), 4.18(q, J=7 Hz, 2H), 3.52-3.78 (m, 4H), 2.78-3.08 (m, 4H), 1.28 (t, J=7 Hz,3H). MS: ESI (positive): 226 (M+H).

e.) 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine

The product of step d) (200 mg, 0.89 mmol) was dissolved in 15 mL CHCl₃and treated with TMSI (4.5 mmol, 600 uL). After heating to 70° C.overnight, the reaction was carefully quenched with MeOH (10 mL) and 1 MNaOH (20 mL). The subtitle compound was extracted into DCM (3×20 mL).The extracts were dried over MgSO₄ and concentrated to give 178 mg ofthe subtitle compound. ¹H NMR (300 MHz, DMSO) 7.20 (d, J=5 Hz, 1H), 6.85(d, J=5 Hz, 1H), 3.42-3.61 (m, 4H), 2.71-3.03 (m, 4H). MS: ESI(positive): 154 (M+H).

f.) 4,5,7,8-Tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid tert-butylester

The product of step e) (296 mg, 1.93 mmol) dissolved in a 50:50 mixtureof acetone/water (8 mL) was treated with NaHCO₃ (340.5 mg, 4.03 mmol) at0° C. and stirred for 30 minutes. To the resulting solution was addeddi-tert-butyl dicarbonate (463 mg, 2.12 mmol). The reaction mixture wasstirred at ambient temperature for 14 hours. The reaction mixture waspoured into water (50 ml) and extracted with EtOAc (3×50 ml). Thecombined organic phases were washed with brine (75 ml), dried (MgSO₄),and concentrated in vacuo to give the crude product as an oil.Purification by silica gel chromatography (EtOAc/Hexane-gradient) gavethe subtitled compound as a clear oil; yield (93%). ¹H NMR (300 MHz,CDCl₃) δ 6.96 (d, J=5 Hz, 1H), 6.76 (d, J=5 Hz, 1H), 3.44-3.68 (m, 4H),2.76-3.06 (m, 4H), 1.50 (s, 9H). MS: ESI (positive): 254 (M+H).

g.) 2-Bromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidtert-butyl ester

The product of step f) (10 mg, 0.039 mmol) dissolved in a 50:50 mixtureof chloroform/acetic acid (1 ml) was treated with N-bromosuccinimide (7mg, 0.041 mmol). The reaction mixture was stirred for 30 minutes atambient temperature. The reaction mixture was poured into water (5 ml)and extracted with CHCl₃(3×5 ml). The combined organic phases werewashed with 10% KOH solution (5 ml), brine (5 ml), dried (MgSO₄), andconcentrated to give the crude product as an oil. Purification by HPLCgave the subtitle compound as an oil. MS: ESI (positive): 332, 334(M+H).

h.) 2-Bromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step g) (0.39 mmol) dissolved in ether (1 ml) was treatedwith 4 M HCl/dioxane (1 ml). The reaction mixture was stirred for 18hours at ambient temperature. The resulting precipitate was filtered andwashed with anhydrous diethyl ether to give the title compound as itsHCl salt. ¹H NMR (300 MHz, DMSO) δ 9.40 (s, 2H), 7.05 (s, 1H), 3.14-3.33(m, 4H), 2.94-3.23 (m, 2H), 2.76-3.06 (m, 2H). MS: ESI (positive): 232,234 (M+H).

Example 2 2-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme1a)

a.) 2-Chloro-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidtert-butyl ester

The product of Example 1, step f) (10 mg, 0.039 mmol, Example 1) inCHCl₃ (1 ml) and HOAc (1 mL) was treated with N-chlorosuccinimide (6 mg,0.041 mmol). The reaction mixture was stirred for 12 hours at ambienttemperature. The reaction mixture was poured into water (5 ml) andextracted with CHCl₃ (3×5 ml). The combined organic phases were washedwith 10% KOH solution (5 ml), brine (5 ml), dried (MgSO₄), andconcentrated to give the crude product as an oil. Purification by HPLCgave the subtitled compound as a clear oil. MS: ESI (positive): 288(M+H).

b.) 2-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a). ¹H NMR (300 MHz, DMSO) δ 6.72 (s, 2H),2.78-2.85 (m, 2H), 2.72-2.79 (m, 4H), 2.51-2.70 (m, 2H). MS: ESI(positive): 188 (M+H).

Example 3 2,3-Dibromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme1b)

a.) 2,3-Dibromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of Example 1, step d) (95 mg, 0.42 mmol) was dissolved inCHCl₃ (1 ml) and HOAc (1 mL) and treated with NBS (66.7 mg, 0.42 mmol).The reaction mixture was stirred for 20 minutes at ambient temperature.To this mixture was added sodium acetate (138 mg, 1.68 mmol) andadditional NBS (133.4 mg, 0.84 mmol). The reaction mixture was stirredat 60° C. until the reaction was complete as determined by LC/MS. Thereaction mixture was cooled to ambient temperature, diluted withsaturated sodium bicarbonate (2 ml), and extracted with CHCl₃ (3×2 ml).The combined organic phases were washed with brine (10 ml), dried(MgSO₄), and concentrated in vacuo to give the product as a crude oil.Purification by flash chromatography (EtOAc/Hexane-gradient) providedthe subtitled compound as an oil. MS: ESI (positive): 384 (M+H).

b.) 2,3-Dibromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step b) (0.42 mmol) was dissolved in DCM (2 ml) andtreated with iodotrimethylsilane (0.46 mmol). The reaction mixture wasstirred at reflux for 24 hours. The reaction mixture was poured intosaturated sodium bicarbonate (10 ml) and extracted with dichloromethane(3×5 ml). The combined organic phases were washed with brine (10 ml),dried (MgSO₄), and concentrated in vacuo to give an oil. Purification bypreparative HPLC provided the title compound. ¹H NMR (300 MHz, CDCl₃) δ2.94-3.05 (m, 4H), 2.85-2.92 (m, 4H), 1.92 (s, 1H). MS: ESI (positive):312 (M+H).

Example 4 2,3-Dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 4)

a.) (4,5-Dichloro-thiophen-2-yl)-oxo-acetic acid ethyl ester

At 5-10° C., Chloro-oxo-acetic acid ethyl ester (5.43 ml, 48.7 mmol) wasadded to 2,3-Dichlorothiophene (5 g, 32.6 mmol). A solution of AlCl₃(6.49 g, 48.7 mmol) dissolved in nitromethane (13 ml) was added dropwisesuch that the internal reaction temperature did not rise above 10° C.After 1 hour, the reaction mixture was poured into ice water andextracted with CH₂Cl₂ (2×100 ml). The organic layer was washed with 10%NaHCO₃ (2×50 ml), water (1×50 ml) and brine (1×50 ml). Drying (Na₂SO₄)and concentration provided a light orange solid that was purified bysilica gel chromatography (EtOAc/hexane-gradient) providing 6.8 g (82%)of the subtitle compound.

b.) (4,5-Dichloro-thiophen-2-yl)-hydroxy-acetic acid ethyl ester

A solution of the product from step a) (23.0 g, 90.9 mmol) in THF (500ml) was treated with NaBH(OAc)₃ (23.1 g, 109 mmol) and AcOH (250 μl) at60° C. for 1 hour. The reaction was quenched with AcOH (8 ml) andconcentrated to ˜250 ml. The contents were diluted with H₂O (400 ml) andextracted with CH₂Cl₂ (1×400 ml; 1×100 ml). The organic layer was dried(MgSO₄) and concentrated providing 23 g of the subtitle compound. ¹H NMR(300 MHz, CDCl₃) δ 6.91 (s, 1H); 5.25 (dd, J₁=6 Hz, J₂=1 Hz, 1H);4.22-4.40 (m, 2H); 3.52-3.60 (br m, 1H); 1.33 (t, J=7 Hz, 3H).

c.) (4,5-Dichloro-3-methoxycarbonylmethyl-thiophen-2-yl)-acetic acidethyl ester

A solution of the product from step b) (12.2 g, 48.0 mmol) in decalin(145 ml) was treated with trimethylorthoacetate (24.5 ml, 192 mmol) andhexanoic acid (0.61 ml). The flask was equipped with a vigreux columnand heated to 180° C. Additional hexanoic acid (3 ml) was periodicallyadded over 6 hours and the reaction was heated overnight. The reactionwas concentrated on the rotavap and the residue was extracted with MeOH(100×2). The MeOH extracts were concentrated and purified by silica gelchromatography (EtOAc/Hexane-gradient) providing 4.36 g (29%) of thesubtitle compound. MS: ESI (positive): 311, 313 (M+H).

d.) (3-Carboxymethyl-4,5-dichloro-thiophen-2-yl)-acetic acid

A solution of the product from step c) (1.14 g, 3.66 mmol) in MeOH (7ml) at 0° C. was treated dropwise with 2M NaOH (3.8 ml). The reactionwas warmed to 22° C. and stirred overnight. The solvent was evaporatedand the residue was dissolved in 2 M NaOH (50 ml) and extracted withether (2×50 ml). The basic layer was cooled to 0° C. and acidified to pH1 with 6 M HCl. The acidic layer was back extracted EtOAc (4×100 ml) andthe organic layer was dried (MgSO₄) and concentrated. The crude solidwas triturated with hexanes and filtered providing 2.75 g (73%) of thesubtitle compound.

MS: ESI (negative): 267, 269 (M−H).

e.) 2-[4,5-Dichloro-3-(2-hydroxy-ethyl)-thiophen-2-yl]-ethanol

A solution of the product from step d) (2.5 g, 9.33 mmol) in THF (85 ml)was cooled to 0° C. and a 1M solution of BH₃-THF (46.6 ml, 46.6 mmol)was added dropwise over 10 minutes, and stirred for an additional 20minutes, after the addition was complete. The reaction was warmed to 22°C. and stirred for 2 hours. The reaction was poured into ice cold sat.NaHCO₃ (150 ml) and extracted with EtOAc. The crude was passed through aplug of silica gel washing with EtOAc. Concentration of the eluentprovided 1.99 g (88%) of the subtitle compound.

f.) Methanesulfonic acid2-[4,5-dichloro-2-(2-methanesulfonyloxy-ethyl)-thiophen-3-yl]-ethylester

A solution of the product from step e) (1.99 g, 8.25 mmol) in CH₂Cl₂ (41ml) was cooled to 0° C. and treated with triethylamine (3.4 ml, 24.7mmol) followed by dropwise addition of methanesulfonyl chloride (1.4 ml,18.1 mmol) over 10 minutes. After 45 minutes, the crude reaction wasdiluted with CH₂Cl₂ (100 ml) and washed with ice water (25 ml), 10%citric acid (2×25 ml), sat. NaHCO₃ (2×25 ml) and brine (1×25 ml). Theorganic layer was dried (MgSO₄), concentrated to 20 ml and diluted withanhydrous dioxane (76 ml). This mixture was concentrated to removeremaining CH₂Cl₂ and the resulting dioxane solution was carried forwardto the next reaction.

g.) 6-Benzyl-2,3-dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The bismesylate dioxane solution generated in step f) was transferred toa 3-neck reaction flask equipped with a dropping funnel and condenser.Anhydrous potassium carbonate (4.93 g, 35.7 mmol) was added and thecontents were heated to reflux. Next, a solution of benzylamine (2.71 g,25.3 mmol) in anhydrous dioxane (27 ml) was added dropwise over 45minutes and heating was continued for 16 hours. The salts were filteredoff and the solvent was concentrated. The crude was purified by silicagel chromatography (EtOAc/Hexane-gradient) providing 1.43 g (62%) of thesubtitle compound. ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.40 (m, 5H); 3.73 (s,2H); 2.68-2.89 (m, 8H); MS: ESI (positive): 312, 314 (M+H).

h.) 2,3-Dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepineHydrochloride

A solution of the product from step g) (727 mg, 2.33 mmol) in anhydrousdichloroethane (11.6 ml) was cooled to 0° C., treated with 1-Chloroethylchloroformate (1.27 ml, 11.65 mmol) and the reaction was warmed to 22°C. for 1 hour. The reaction diluted with CH₂Cl₂ (50 ml) and washed withsat. NaHCO₃ (25 ml). The sat. NaHCO₃ was back extracted with CH₂Cl₂ andthe combined organic layers were washed with brine (25 ml), dried(MgSO₄) and concentrated providing an oily residue, which was taken upin anhydrous MeOH (75 ml) and refluxed for 1 hour. The MeOH wasevaporated and the crude residue was triturated with ether and filteredproviding 323 mg (5400) of the subtitle compound. ¹H NMR (300 MHz, DMSO)δ 9.60 (br s, 2H); 3.14-3.28 (m, 6H); 2.97-3.50 (m, 2H); MS: ESI(positive): 222, 224 (M+H).

Example 5 2-Bromo-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 1b)

a.)2-Bromo-3-chloro-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The product of Example 1, step f) (54 mg, 0.21 mmol) was dissolved inCHCl₃ (1 ml) and HOAc (1 mL) and treated with hydroquinone (2 mg, 0.02mmol) and N-bromosuccinimide (38 mg, 0.21 mmol). After stirring atambient temperature for 20 minutes, N-chlorosuccinimide (28 mg, 0.21mmol) was added and stirring was continued at ambient temperature for 48hours. The reaction mixture was poured into saturated sodium bicarbonate(10 ml) and extracted with chloroform (3×5 ml). The combined organicphases were washed with brine (10 ml), dried (MgSO₄) and concentratedproviding a crude oil, which was used without further purification.

b.) 2-Bromo-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepineHydrochloride

The title compound was prepared by the method of Example 1 step h),using the product of step a). ¹H NMR (300 MHz, DMSO) δ 9.12 (bs, 2H);3.22-3.31 (m, 4H); 3.13-3.20 (m, 2H); 2.98-3.05 (m, 2H). MS: ESI(positive): 266, 268 (M+H).

Example 62-(4-Triflouromethoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 2)

a.)2-(4-Trifluoromethoxy-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The product of Example 1, step g) (20 mg, 0.06 mmol) was dissolved inDME (5 mL) and treated with palladium acetate (1 mg, 0.004 mmol),triphenylphosphine (4.7 mg, 0.018 mmol) and 1 M sodium carbonate(Na₂CO₃; 0.45 mL). The mixture was stirred at ambient temperature for 5minutes and then treated with 4-trifluoromethoxy phenylboronic acid(28.4 mg, 0.138 mmol). After heating for 5 hours at 85° C., additional4-trifluoromethoxy phenyl-boronic acid (6.2 mg, 0.03 mmol) was added andstirring continued for 12 hours. The reaction mixture was cooled toambient temperature, passed through a pad of dry celite and filteredthrough a silica plug eluting with DCM (5 ml) and EtOAc (5 mL). Thefiltrate was evaporated to give the subtitle compound as a crude oil,which was used without further purification.

b.)2-(4-Trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a). The reaction mixture was concentrated invacuo and purified by preparative HPLC to give the title compound. ¹HNMR (300 MHz, DMSO) δ 7.76 (d, J=8 Hz, 2H), 7.48 (d, J=8 Hz, 2H), 7.36(s, 1H), 2.77-3.06 (m, 8H), 2.0 (s, 1H).) MS: ESI (positive): 314 (M+H).

Example 72-(2-Trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 2)

a.)2-(2-Trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using 2-trifluoromethyl-phenyl boronic acid.

b.)2-(2-Trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a). The reaction mixture was concentrated invacuo and purified by preparative HPLC to give the title compound. MS:ESI (positive): 298 (M+H).

Example 8 2-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 2)

a.)2-(4-Fluoro-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using 4-fluorophenyl boronic acid.

b.) 2-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a). The reaction mixture was concentrated invacuo and purified by preparative HPLC to give the title compound. MS:ESI (positive): 248 (M+H).

Example 92-(3-Chloro-4-fluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 2)

a.)2-(3-Chloro-4-fluoro-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using 3-chloro-4-fluorophenyl boronic acid.

b.)2-(3-Chloro-4-fluoro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine:

The title compound was prepared by the method of Example 1 step h),using the product of step a). The reaction mixture was concentrated invacuo and purified by preparative HPLC to give the title compound. MS:ESI (positive): 282 (M+H).

Example 102-(2,5-Dichloro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 2)

a.)2-(2,5-dichloro-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using 2,4-dichlorophenyl boronic acid.

b.) 2-(2,5-Dichloro-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a). The reaction mixture was concentrated invacuo and purified by preparative HPLC to give the title compound. MS:ESI (positive): 298 (M+H).

Example 11 2-(4-Ethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 2)

a.)2-(4-Ethyl-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using 4-ethylphenyl boronic acid.

b.) 2-(4-Ethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a) except the reaction mixture wasconcentrated in vacuo and purified by preparative HPLC to give the titlecompound. MS: ESI (positive): 258 (M+H).

Example 122-(3-Methoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme2)

a.)2-(3-Methoxy-phenyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using 3-methoxyphenyl boronic acid.

b.) 2-(3-Methoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a) except the reaction mixture wasconcentrated in vacuo and purified by preparative HPLC to give the titlecompound. MS: ESI (positive): 260 (M+H).

Example 13 2-Phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme2)

a.) 2-Phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-6-carboxylicacid tert-butyl ester

The subtitle compound was prepared by the method of Example 6 step a),using phenyl boronic acid.

b.) 2-Phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 1 step h),using the product of step a) except the reaction mixture wasconcentrated in vacuo and purified by preparative HPLC to give the titlecompound. MS: ESI (positive): 230 (M+H).

Example 142-(2-Chloro-6-fluoro-benzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 3)

a.) 2-Bromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

The product of Example 1, step d) (300 mg, 1.33 mmol) was dissolved inchloroform (3 ml) and acetic acid (3 ml) and treated withN-bromosuccinimide (248 mg, 1.40 mmol) and stirred at ambienttemperature for 30 minutes. The reaction mixture was carefully quenchedby dilution with saturated sodium bicarbonate (20 ml) and extracted withchloroform (3×20 ml). The combined organic phases were washed with brine(50 ml), dried (MgSO₄), and evaporated in vacuo to give a crude oil.Purification by preparative TLC (hexane/ethyl acetate) provided thesubtitle compound as an oil. MS: ESI (negative): 302 (M−H).

b.)2-(2-Chloro-6-fluoro-benzyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step a) (144 mg, 0.48 mmol) in 2 ml dry diethyl ether wastreated with NiCl₂(dppp) (3-5 mol %) followed by dropwise addition of2-chloro-6-fluorobenzyl magnesiumbromide (0.25 M solution, 1.2 mmol, 4.8ml) over 30 minutes at ambient temperature. The reaction mixture washeated to reflux for 12 hours. The reaction mixture was cooled toambient temperature, quenched with 1M HCl (10 ml) and extracted withdiethyl ether (3×10 ml). The combined ether extracts were washed withwater (30 ml), dried (MgSO₄), and evaporated providing a crude oil.Purification by HPLC provided the subtitle compound. MS calculated forC₁₈H₁₉ClFNO₂S+H 369, observed 369.

c.)2-(2-Chloro-6-fluoro-benzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 3 step b),using the product of step b). ¹H NMR (300 MHz, C₆D₆) δ 6.94 (d, J=8 Hz,1H), 6.52-6.70 (m, 2H), 6.49 (s, 1H), 4.17 (s, 2H), 2.47-2.78 (m, 8H),2.03 (s, 1H). MS: ESI (positive): 296 (M+H).

Example 153-Bromo-2-(2-chloro-6-fluoro-benzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 3)

a.)3-Bromo-2-(2-chloro-6-fluoro-benzyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of Example 14, step b) (49 mg, 0.13 mmol) was dissolved in a1:1 mixture of CHCl₃/HOAc (1 mL) and treated with sodium acetate (43 mg,0.52 mmol) and N-bromosuccinimide (27 mg, 0.15 mmol). The reactionmixture was heated at 60° C. and stirred for 30 minutes. The reactionmixture was cooled to ambient temperature, diluted with water (5 ml),and extracted with chloroform (3×5 ml). The combined organic extractswere washed with 10% KOH, dried (MgSO₄), and evaporated in vacuo to givethe subtitle compound as an oil, which was used without furtherpurification.

b.)3-Bromo-2-(2-chloro-6-fluoro-benzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method of Example 3 step b),using the product of step a). ¹H NMR (300 MHz, C₆D₆) δ 6.33-6.78 (m,3H), 4.09 (s, 2H), 2.18-3.20 (m, 8H), 1.62 (s, 1H). MS calculated forC₁₅H₁₄BrClFNS+H 374, observed 374.

Example 16 2-Bromo-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 4)

a.) (5-Bromo-4-methyl-thiophen-2-yl)-hydroxy-acetic acid ethyl ester

2-Bromo-3-methyl thiophene (13.2 mL, 113 mmol) was stirred in 1 liter ofDCM at 0° C. Ethylchloro oxalate (13.9 mL, 124 mmol) was added followedby AlCl₃ (16.5 g, 124 mmol). After stirring for 10 minutes, the reactionwas carefully poured over ice (˜500 mL) and EtOH (˜300 mL). Upon warmingto room temperature, the product was extracted into DCM (2×) and driedover MgSO₄. Concentration gave 37.5 g of an orange solid which wasdissolved in THF (1 liter) and treated with NaBH(OAc)₃ (36 g, 170 mmol).After heating to 60° C. for 1 hour, the reaction was cooled and quenchedwith HOAc (13.6 mL, 226 mmol). The reaction was concentrated and theresidue was partitioned between DCM/EtOH (5:1) and water. The aqueouslayer was extracted 1× with DCM and the combined organic extracts weredried over MgSO₄ and concentrated to give the subtitle compound (35 g),which was used without further purification.

b.) (5-Bromo-3-ethoxycarbonylmethyl-4-methyl-thiophen-2-yl)-acetic acidethyl ester

The product of step a) (˜113 mmol) was treated with 300 mL decalin, 103mL of triethylorthoacetate (565 mmol), and hexanoic acid (6.2 mL, 50mmol). The reaction was heated to 180° C. for 10 minutes after whichtime another 50 mmol of hexanoic acid was added. After heating 10minutes, additional hexanoic acid was added (50 mmol) and the reactionwas again heated for 10 minutes. The reaction was cooled andconcentrated under vacuum with heat to give the sub-title compound as anoil that was used without further purification.

c.) 2-[5-Bromo-3-(2-hydroxy-ethyl)-4-methyl-thiophen-2-yl]-ethanol

The product of step b) (−113 mmol) was dissolved in EtOH (1 liter) andcooled to 0° C. then treated with 170 mL of 2M NaOH. After stirring for24 hours, the resulting precipitate was filtered and washed with ethanolto give 15 g of the disodium salt. A portion of this material (3 g, 8.9mmol) was dissolved in 90 mL THF and treated with 4M HCl in dioxane (4mL, 16 mmol). After stirring vigorously for ½ hour, BH₃-THF (44.4 mL of1M) was added and the solution was stirred at room temperature for 2hours. The reaction was quenched cautiously with saturated NaNCO₃ andconcentrated. The crude residue was partitioned between EtOAc and water(150 mL each). The organic layer was dried over MgSO₄ and concentratedto give 1.94 g of the sub-title compound.

d.) 6-Benzyl-2-bromo-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step c) (1.94 g, 7.3 mmol) was dissolved in 75 mL of DCM,cooled to 0° C. and treated with Et₃N (29.3 mmol, 4.1 mL) followed byMsCl (22 mmol, 1.71 mL). After 1 hour, additional Et₃N and MsCl wereadded (2 eq and 1.5 eq, respectively) and the reaction was stirred anadditional hour. The crude reaction was poured over 5% citric acid,extracted into DCM, and washed with saturated NaHCO₃. After drying theorganic solution over MgSO₄ and concentration, the crude product wasdissolved in dioxane (200 mL) and treated with K₂CO₃ (36.6 mmol, 5.0 g).After heating to reflux, BnNH₂ (22 mmol, 2.4 mL) was added and thereaction was refluxed overnight. The reaction was cooled, filtered, andconcentrated. The sub-title compound was purified by silica gelchromatography (10% EtOAc in hexanes) to give 419 mg of the subtitlecompound.

e.) 2-Bromo-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step d) (80 mg, 0.24 mmol) was dissolved in 2 mL DOE.2-Chloroethyl chloroformate (103 uL, 0.95 mmol) was added and thereaction was stirred at room temperature for 15 minutes. The reactionwas quenched with 3 mL MeOH and the crude mixture was briefly heated toreflux and then concentrated to dryness. The crude residue was dissolvedin ½ mL of MeOH and triturated with ether to give 47 mg of the titlecompound as a white solid. ¹H NMR (CD₃OD) δ 3.36-3.30 (m, 4H), 3.12 (t,J=5.2 Hz, 2H), 3.00 (t, J=5.1 Hz, 2H), 2.11 (s, 3H); MS: ESI (positive):246,248 (M+H).

Example 17 3-Methoxy-2-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 5)

a.) 5-Oxo-azepane-1,4-dicarboxylic acid diethyl ester

4-Oxo-piperidine-1-carboxylic acid ethyl ester (20 g, 117 mmol) wasdissolved in 120 mL Et₂O and cooled to −30° C. BF₃—OEt₂ (14.8 mL) andethyl diazoacetate (16 mL, 152 mmol) were added simultaneously (each in15 mL Et₂O) over the course of 30 minutes, maintaining an internaltemperature of approximately −20° C. The reaction was warmed to roomtemperature and stirred for 3 hours after which time the reaction wasquenched carefully with 30% K₂CO₃ (60 mL). The organic layer was driedover K₂CO₃ and concentrated to give 30.4 g of the subtitle compound.

b.) 3-Hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-2,6-dicarboxylicacid diethyl ester

The product of step a) (20 g, 77.8 mmol) was dissolved in 300 mL EtOH.The solution was cooled to 0° C. and HCl gas was bubbled into thereaction for 10 minutes. Ethyl thioglycolate (7.8 mL, 77.8 mmol) wasadded and HCl gas was again bubbled into the solution for 3 minutes.After stirring for 4 days at room temperature, the reaction wasconcentrated, neutralized with saturated NaHCO₃, and extracted intoether (200 mL). After drying the extracts over MgSO₄ and concentration,the residue was dissolved in EtOH (100 mL) and treated with NaOEt (100mL of 21% NaOEt in EtOH). After stirring overnight, the reaction wasdiluted with 500 mL water and washed with 300 mL DCM. The DCM wasextracted with 150 mL water and then repeatedly extracted with 5% KOH(−10×75 mL). The combined aqueous extracts were acidified withconcentrated HCl and extracted into DCM (4×200 mL). The DCM extractswere dried over MgSO₄ and concentrated to give 7.5 g of the subtitlecompound as an oil.

c.) 3-Methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-2,6-dicarboxylicacid diethyl ester

The product of step b) (2.3 g, 7.3 mmol) was dissolved in 60 mL of 1:1MeOH:THF. Diisopropylethylamine (1.9 mL, 10.9 mmol) was added followedby TMSCHN₂ (10.9 mL of 2M). The reaction was stirred overnight at roomtemperature then quenched carefully with 0.4 mL HOAc. After stirring ½hour, the reaction was partitioned between DCM and 1M HCl (100 mL each).The organic layer was dried over MgSO₄ and concentrated to give 2.75 gof the subtitle compound.

d.)2-Hydroxymethyl-3-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step c) (2.5 g, 7.8 mmol) was dissolved in 125 mL dry THFand treated with LiCl (0.65 g, 15.3 mmol) followed by LiBH₄ (15.3 mL of2M). After stirring for 1 hour, the reaction was quenched carefully withEtOH and HOAc till no gas evolution was observed. The crude reactionmixture was partitioned between water and DCM. The organic extract wasdried over MgSO₄ and concentrated to give 2.3 g of a clear oil which waspurified by silica chromatography (30% EtOAc/Hex) to give 1.03 g of thesubtitle compound.

e.) 3-Methoxy-2-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step d) (70 mg, 0.25 mmol) was dissolved in 10 mL EtOAcand treated with 35 mg of 10% Pd/C (wet, Degussa type E101) and stirredrapidly under an atmosphere of H₂ for 3 hour. The reaction was filteredand concentrated. The crude residue was dissolved in 1 mL EtOH andtreated with 1 mL 40% aqueous KOH. After heating to 80° C. overnight,the reaction was diluted with water and the product was extracted 2×into DCM. The title compound was obtained upon purification bypreparative HPLC-MS. ¹H NMR (CDCl₃) δ 3.69 (s, 3H), 3.21-3.14 (m, 4H),3.00 (t; J=5.2 Hz, 2H), 2.88 (t, J=5.1 Hz, 2H), 2.29 (s, 3H); MS: ESI(positive): 198 (M+H).

Example 18 2-Bromo-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 5)

a.) 3-Methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-2,6-dicarboxylicacid 6-ethyl ester

The product from Example 17, step c) (1.0 g, 3.19 mmol) was stirred inethanol (20 mL) with 1M NaOH (6.38 mL, 6.38 mmol) at 80° C. overnight.The reaction was cooled to ambient temperature, acidified with a 10% HClsolution, and extracted with 5% EtOH in DCM (×2). The organic extractswere combined and washed with water. The organic layer was dried overNaSO₄, filtered, and concentrated to give 912 mg of the subtitledcompound that was used without further purification. MS: ESI (positive):300 (M+H).

b.)2-tert-Butoxycarbonylamino-3-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step a) (790 mg, 3.01 mmol) was stirredwith diphenylphosphoryl azide (647 μL, 3.01 mmol) and triethylamine (418μL, 3.01 mmol) in tert-butanol (20 mL) at 80° C. overnight. The reactionwas cooled to room temperature and poured into a saturated aqueoussolution of NaHCO₃. The resultant mixture was extracted with ethylacetate. The organic extract was dried over MgSO₄ and purified by silicagel chromatography (EtOAc/Hex-gradient) to give 852 mg of the subtitlecompound. MS: ESI (positive): 370 (M+H).

c.) 3-Methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

The product from step b) (256 mg, 0.69 mmol) was stirred in TFA (2 mL)for 30 minutes. The reaction was concentrated and dissolved in EtOH (5mL). Isoamyl nitrite (140 μL, 1.04 mmol) and Cu(OAc)₂ (188 mg, 1.04mmol) were added to the solution and the reaction was stirred at roomtemperature overnight. The reaction was filtered through a silica plugand purified by silica gel chromatography (EtOAc/Hex-gradient) to give17 mg of the subtitle compound. MS: ESI (positive): 271 (M+H).

d.)2-Bromo-3-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step c) (17 mg, 0.067 mmol) was dissolved in 1 mL 1:1acetic acid:CHCl₃ and treated with N-bromosuccinimide (12 mg, 0.068mmol). After 30 minutes, the reaction solution was added dropwise to asolution of saturated sodium bicarbonate and extracted with ethylacetate. The organic extracts were concentrated to give the subtitlecompound, which was used without further purification.

e.) 2-Bromo-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

A 40% KOH solution in water (1 mL) was added to the product of step d)(˜0.067 mmol) in 1 mL ethanol. After heating to 80° C. overnight, thereaction mixture was cooled to ambient temperature and partitionedbetween water and DCM. The organic extract was concentrated and purifiedby preparative LCMS to give the title compound. ¹H NMR (CD₃OD) δ 3.83(s, 3H), 3.22-3.28 (m, 4H), 3.05 (t, J=5.1 Hz, 2H), 2.93 (t, j=5.1 Hz,2H); MS: ESI (positive): 262 (M+H).

Example 19 2-Chloro-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 5)

a.)2-Chloro-3-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The sub-title compound was prepared by the method of Example 18, step d)using the product from Example 18, step c) and N-chlorosuccinimide.

b.) 2-Chloro-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method described in Example 18,step e) using the product from step a). ¹H NMR (CD₃OD) δ 3.86 (s, 3H),3.19-3.26 (m, 4H), 3.01 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.4 Hz, 2H). MS:ESI (positive): 218 (M+H).

Example 202-Isopropenyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 5)

a.)2-Isopropenyl-3-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of Example 17, step c) (59 mg, 0.19 mmol) was dissolved in 5mL THF and cooled to 0° C. MeMgBr (0.54 mL of 1.4M) was added and thereaction was stirred at room temperature for 1 hour. The reaction wasquenched with water and HOAc (˜3 mL of 10:1) and extracted into DCM (2×5mL). The organic extracts were concentrated to give the sub-titlecompound as an oil, which was used without further purification.

b.) 2-Isopropenyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step a) (˜0.19 mmol) was treated with 2 mL each of EtOHand 40% aqueous KOH. After heating to 100° C. for 16 hours, the reactionwas diluted with water and the product was extracted into DCM (2×4 mL).The organic extracts were concentrated and the title compound waspurified by preparative HPLC-MS. ¹H NMR (CD₃OD) δ 5.41 (s, 1H), 5.02 (t,J=1.6 Hz, 1H), 3.14-3.08 (m, 4H), 2.98 (t, J=5.1 Hz, 2H), 2.82 (t, J=5.1Hz, 2H), 2.09 (s, 3H); MS: ESI (positive): 224 (M+H).

Example 212-tert-Butyl-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme9)

a.) 3-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

The product of Example 16, step e) (475 mg, 1.68 mmol) was dissolved in50 mL DCM and treated with Et₃N (585 uL, 4.2 mmol) and ethylchloroformate (210 uL, 2.18 mmol). After stirring for 3 days at roomtemperature, the reaction was concentrated onto silica gel and purifiedby silica gel chromatography (EtOAc/Hex-gradient) to give 380 mg of theethyl carbamate. The ethyl carbamate (60 mg, 0.19 mmol) was dissolved in4 mL EtOH and treated with ˜10 mg of 10% Pd/C (wet, Degussa grade E101)and stirred under an atmosphere of hydrogen for 12 hours. Filtration andconcentration gave the sub-title compound.

b.)2-tert-Butyl-3-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step a) (37 mg, 0.16 mmol) was stirred in 1.5 mL DCE.t-Butanol (19 uL, 0.20 mmol) was added followed by BF₃-OEt₂ (20 uL, 0.16mmol). The reaction was heated to 60° C. for 1 hour. Concentration gavethe subtitle compound, which was used without further purification.

c.) 2-tert-Butyl-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step b) was treated with 2 mL each of EtOH and 40%aqueous KOH. After heating to 100° C. for 12 hours, the reaction wascooled, diluted with water, and extracted 2× into DCM. The title productwas purified by preparative HPLC-MS. MS: ESI (positive): 224 (M+H).

Example 222-Isopropyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme5)

a.)2-Isopropyl-3-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of Example 20, step a) (35 mg, 0.13 mmol) was dissolved in 2mL of EtOH and treated with 50 mg of 10% Pd/C (wet, Degussa grade E101).After stirring 3 hours at room temperature under an atmosphere ofhydrogen, the reaction was filtered and concentrated to give thesubtitle compound as an oil.

b.) 2-Isopropyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step a) was deprotected according to the proceduredescribed for Example 20, step b). Purification by preparative HPLC-MSgave the title compound. ¹H NMR (CD₃OD) (δ 3.69 (s, 3H), 3.29-3.21 (m,5H), 3.03 (t, J=5.2 Hz, 2H), 2.88 (t, J=5.4 Hz, 2H), 1.24 (d, J=6.9 Hz,6H); MS: ESI (positive): 226 (M+H).

Example 23 2-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 6)

a.) 4-Methylene-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

Methyl triphenylphosphonium bromide (6.3 g, 17.6 mmol) was dissolved in150 mL THF and cooled to 0° C. KHMDS (3.2 g, 16.2 mmol) was addedportionwise and the reaction was stirred for ½ hour. The product ofExample 1, step c) (3.0 g, 12.5 mmol) was added as a solution in 25 mLTHF. The reaction was warmed to room temperature and stirred for 1 hour.The mixture was concentrated and the title product was purified bysilica gel chromatography (EtOAc/Hexanes-gradient) to give 2.6 g of thesubtitle compound.

b.) 4-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

The product of step a) (2.6 g, 10.8 mmol) was dissolved in 100 mL EtOHand treated with 0.5 g of 10% Pd/C (wet, Degussa type E101). Afterstirring rapidly for 14 hours under an atmosphere of hydrogen, thereaction was filtered through celite and concentrated to give 2.3 g ofthe subtitle compound as a clear oil. MS: ESI (positive): 240 (M+H).

c.)2,3-Dibromo-4-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step b) (5.6 g, 23.4 mmol) was dissolved in 250 mLcyclohexane and treated with NaHCO₃ (11.8 g, 140 mmol). Bromine (3.6 mL,70.3 mmol) was added slowly and the reaction was stirred for ½ hour atroom temperature after which time it was quenched with Na₂SO₃ (180 mL of5% aqueous). After stirring rapidly for 15 minutes, EtOAc was added(−100 mL) and the organic layer was removed and dried over MgSO₄ to give9.1 g of the sub-title compound. The racemic material was separatedusing a Chiralpak® AD-RHO 20×250 mm column from Chiral Technologies (10mL/min MeOH mobile phase) to give enantiomer 1 (rt=9.8 minutes) andenantiomer 2 (rt=11.4 minutes) of the subtitle compound.

d.) 4-Methyl-4,5,7,8-tetrahydro-thieno(2,3-diazepine-6-carboxylic acidethyl ester

The product of step c) (800 mg, 2.0 mmol) was dissolved in 150 mL EtOHand treated with 800 mg of 10% Pd/C (wet, Degussa grade E101). Afterstirring overnight, another 300 mg of Pd was added and stirring wascontinued 3 hours. The reaction was filtered through celite, dilutedwith DCM (300 mL), and washed with water (1×300 mL). The organic layerwas dried over MgSO₄ and concentrated to give 475 mg of the subtitlecompound.

e.)2-Bromo-4-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1CHCl₃/HOAc. N-Bromo-succinimide (62 mg, 0.35 mmol) was added and thereaction was stirred for 15 minutes. Concentration and purification bysilica gel chromatography gave the subtitle compound as a yellow oil.

f.) 2-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step e) was deprotected according to the proceduredescribed for Example 20, step b) to provide the title compound. ¹H NMR(CD₃OD) δ6.97 (s, 1H), 3.46-3.11 (m, 7H), 1.39 (d, J=7.2 Hz, 3H); MS:ESI (positive): 246, 248 (M+H).

Example 24 2-Bromo-8-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 7)

a.) 2-Thiophen-3-yl-ethylamine

Thiophen-3-yl-acetonitrile (5.0 g, 40.6 mmol) was dissolved in 50 mLTHF. BH₃-THF (61 mL, 1M in THF) was added slowly. The reaction washeated to 60° C. overnight then quenched carefully with 4% aqueous HCluntil no effervescence was observed. The crude reaction mixture was thenpartitioned between EtOAc and water (300 mL each). The aqueous layer wasacidified with 30% NaOH to pH ˜12 and the product was extracted intoDCM/EtOH (4:1, 3×). The organic extracts were dried over MgSO₄ andconcentrated to give 2.9 g of the subtitle compound as an oil.

b.) [Ethoxycarbonyl-(2-thiophen-3-yl-ethyl)-amino]-acetic acid ethylester

The subtitle compound was prepared from the product of step a) using theprocedure described in Example 1, step a).

c.) [Ethoxycarbonyl-(2-thiophen-3-yl-ethyl)-amino]-acetic acid

The subtitle compound was prepared from the product of step b) using theprocedure described for Example 1, step b).

d.) 8-Oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

The subtitle compound was prepared from the product of step c) using theprocedure described for Example 1, step c).

e.) 8-Methylene-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

MePPh₃Br (785 mg, 2.2 mmol) was dissolved in 7 mL THF and treated withKHMDS (408 mg, 2.04 mmol). After stirring for 30 minutes, the product ofstep d) (350 mg, 1.5 mmol) was added as a solution in 3 mL THF. Afterstirring for 1 hour, the reaction was diluted with EtOAc and washed withwater. The organic layer was concentrated and the product was purifiedby silica gel chromatography (EtOAc/Hex-gradient) to give 188 mg of thesubtitle compound.

f.) 8-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

The product of step a) (59 mg, 0.25 mmol) was dissolved in 5 mL EtOH andtreated with 75 mg of 10% Pd/C (wet, Degussa grade E101). After stirringfor 1 hour under an atmosphere of hydrogen, the reaction was filteredand concentrated to give the subtitle compound that was used withoutfurther purification.

c.) 2-Bromo-8-methyl-5.6.7.0-tetrahydro-4H-thieno[2,3-d]azepine

The product of step f) was dissolved in 2 mL of 1:1 CHCl₃/HOAc andtreated with NBS (62 mg, 0.35 mmol). After stirring for 10 minutes, thereaction was concentrated to dryness and filtered through a pad ofsilica gel, eluting with EtOAc. The eluent was concentrated and theresidue was treated with 2 mL each EtOH and 40% aqueous KOH. Afterheating for 14 hours at 100° C., the reaction was diluted with water andextracted 2× into DCM. The title compound was purified by preparativeHPLC-MS. The two enantiomers were separated using a Chiralpak® AD-RHO20×250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase)to give enantiomer 1 (rt=11.6 minutes) and enantiomer 2 (rt=13.6minutes) of the title compound. ¹H NMR (CD₃OD) δ 6.92 (s, 1H), 3.48-3.34(m, 3H), 3.17-2.99 (m, 4H), 1.44 (d, J=7.2 Hz, 3H); MS: ESI (positive):246, 248 (M+H).

Example 252-Bromo-8-spirocyclopropyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 7)

a.)8-Spirocyclopropyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of ZnCl₂ (2.49 mL, 1M in hexane) and CH₂I₂ (100 μL, 1.24mmol) were stirred at 0° C. in DCM for 30 minutes. The product fromExample 24, step e) (59 mg, 0.25 mmol) was added as a solution in DCM (1mL) and the reaction was stirred at ambient temperature for 48 hours.The reaction was diluted with water and extracted into DCM. The organiclayer was washed with saturated NH₄Cl, water, and brine. Concentrationof the organic layer gave the sub-title compound, which was used withoutfurther purification. MS: ESI (positive): 252 (M+H).

b.)2-Bromo-8-spirocyclopropyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The subtitle compound was prepared by the method described in Example18, step d) using the product from step a) and was used in crude formwithout purification. MS: ESI (positive): 330 (M+H).

c.)2-Bromo-8-spirocyclopropyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method described in Example 18,step e) using the product from step b). ¹H NMR (CD₃OD) 60.84 (s, 1H),3.20 (t, J=5.1 Hz, 2H), 3.02 (t, J=5.1 Hz, 2H), 3.06 (s, 2H), 1.08 (d,J=9.6 Hz, 2H), 1.05 (d, J=9.6 Hz, 2H). MS: ESI (positive): 258 (M+H).

Example 262-(Pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 8)

a.)2-Chlorosulfonyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of Example 1, step d) (400 mg, 1.8 mmol) was dissolved in 10mL CHCl₃ and treated with chlorosulfonic acid (355 uL, 1.8 mmol). After5 minutes, the reaction was quenched over ice and immediately extractedinto DCM (2×10 mL). The organic extracts were dried over MgSO₄ andconcentrated to give 200 mg of the subtitle compound as a solid, whichwas used without further purification.

b.)2-(Pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step a) (45 mg, 0.14 mmol) was stirred in 2 mL CHCl₃ andtreated with pyrrolidine (46 uL. mmol). After stirring for 5 minutes,the reaction was concentrated to dryness and the residue was dissolvedin 2 mL each of EtOH and 40% aqueous KOH. The reaction was heated in asealed vessel to 100° C. overnight. Upon cooling, the reaction wasdiluted with water and the product was extracted into DCM (4×3 mL). Theorganic extracts were concentrated and the title compound was purifiedby preparative HPLC-MS. ¹H NMR (CD₃OD) δ 7.42 (s, 1H), 3.43-3.34 (m,4H), 3.31-3.24 (m, 6H), 3.13 (t, J=5.2 Hz, 2H), 1.81-1.76 (m, 4H); MS:ESI (positive): 287 (M+H).

Example 27 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic aciddimethylamide (Scheme 8)

The title compound was prepared according to the procedure outlined inExample 26, step b) using dimethyl amine hydrochloride and Et₃N. ¹H NMR(CD₃OD) δ 7.38 (s, 1H), 3.44-3.27 (m, 4H), 3.32-3.26 (m, 2H), 3.17-3.14(m, 2H), 2.72 (s, 6H); MS: ESI (positive): 261 (M+H).

Example 283-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic aciddimethylamide (Scheme 8)

a.)2-Chlorosulfonyl-3-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The subtitled compound was prepared according to the procedure outlinedin Example 26, step a) using the intermediate from Example 21, step a).The product was used without further purification.

b.) 3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic aciddimethylamide

The title compound was prepared according to the procedure outlined forExample 26, step b) using the product from step a) and dimethyl aminehydrochloride and Et₃N. ¹H NMR (CD₃OD) δ 3.41-3.35 (m, 4H), 3.24 (dd,J=5.1, 6.6 Hz, 2H), 3.04 (t, J=5.2 Hz, 2H), 2.75 (s, 6H), 2.41 (s, 3H);MS: ESI (positive): 275 (M+H).

Example 29 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic acidcyclopentylamide (Scheme 8)

a.)2-Cyclopentylcarbamoyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product from Example 1, step d) (50 mg, 0.222 mmol) was stirred withisocyanato-cyclopentane (25 μL, 0.222 mmol) and AlCl₃ (35 mg, 0.266mmol) in dichloroethane (2 mL) at ambient temperature for 4 hours.Additional isocyanato-cyclopentane (25 μL, 0.222 mmol) and AlCl₃ (35 mg,0.266 mmol) were added and the reaction was stirred overnight. Thereaction was partitioned between water and DCM. The organic layer waswashed with water and concentrated to give the sub-title compound, whichwas used without further purification. MS: ESI (positive): 337 (M+H).

b.) 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic acidcyclopentylamide

The product from step b) (37 mg, 0.111 mmol) was treated with TMSI (50μL, 0.333 mmol) in DCM (2 mL) and stirred at 50° C. overnight. Thereaction was then treated with methanol (1 mL), concentrated to dryness,and purified by preparative LC-MS to give the title compound. MS: ESI(positive): 265 (M+H).

Example 30 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic aciddimethylamide (Scheme 8)

a.)2-Dimethylcarbamoyl-4,5,7,8-tetrahydro-thieno(2,3-diazepine-6-carboxylicacid ethyl ester

The product from Example 1, step d) (50 mg, 0.22 mmol) was stirred indichloroethane with phosgene iminium chloride (84 mg, 0.518 mmol) andAlCl₃ (35 mg, 0.266 mmol) at 75° C. overnight. The reaction was cooledto ambient temperature, quenched with water (2 mL) and extracted intoDCM. The organic layer was then passed through a pad of celite andconcentrated to give the subtitle compound that was used without furtherpurification. MS: ESI (positive): 297 (M+H).

b.) 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic aciddimethylamide

The title compound was prepared by the method described in Example 29,step b) using the product from step a). MS: ESI (positive): 225 (M+H).

Example 31(R,S)-2-Chloro-8-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 7)

The title compound was prepared from the intermediate described inExample 24, step f) and N-chloro succinimide using the procedure fromExample 24, step g). MS: ESI (positive): 202, 204 (M+H).

Example 322,3-Dibromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme6)

The product of Example 23, step c) was deprotected by the proceduredescribed in Example 20, step b) to provide the title compound. ¹H NMR(CD₃OD) δ 3.60-3.52 (m, 3H), 3.35-3.11 (m, 4H), 1.33 (d, J=6.9 Hz, 3H);MS: ESI (positive): 324, 326, 328 (M+H).

Example 33(R,S)-2-Bromo-4-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 6)

a.) (R,S)-4-Hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

Sodium borohydride (154 mg, 4.18 mmol) was added to a solution of theproduct from Example 1, step c) (200 mg, 0.837 mmol) in ethanol (2 mL)and stirred at ambient temperature for 30 minutes. The reaction wasquenched with acetic acid and partitioned between DCM and water. Theorganic layer was washed with water and concentrated to give thesubtitle compound, which was used without further purification. MS: ESI(positive): 264 (M+Na).

b.) (R,S)-4-Methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product from step a) (160 mg, 0.664 mmol) in anhydrous THF (2.0 mL)was cooled to −78° C. A solution of 1M LHMDS in THF (800 μL, 0.797 mmol)was added to the solution and the reaction was warmed to roomtemperature. MeI (63 μL, 0.996 mmol) was added to the reaction andstirred at ambient temperature for 72 hours. The reaction waspartitioned between ethyl acetate and water and the organic layer wasconcentrated to give the subtitle compound that was purified by silicagel chromatography (EtOAc/Hex-gradient) prior to use in subsequentsteps. MS: ESI (positive): 278 (M+Na).

c.)(R,S)-2-Bromo-4-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The subtitle compound was prepared by the method of Example 18, step d)using the product from step b).

d.) (R,S)-2-Bromo-4-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method described in Example 18,step e) using the product from step c). MS: ESI (positive): 262 (M+H).

Example 342-Bromo-8,8-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme7)

a.) 8,8-Dimethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

DCM (5 mL) was cooled to −78° C. and treated with TiCl₄ (274 uL, 2.5mmol) followed by Me₂Zn (1.3 mL of 2M solution in toluene). Afterstirring the dark red solution at −78° C. for 15 minutes, the product ofExample 24, step d) (100 mg, 0.42 mmol) was added slowly as a solutionin 5 mL DCM. The reaction was warmed to 0° C. and stirred for 2 hours.The reaction was quenched over ice and the product was extracted intoDCM (2×). The organic extracts were dried over MgSO₄ and concentrated togive the subtitle compound, which was used without further purification.

b.) 2-Bromo-8,8-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step a) (45 mg, 0.18 mmol) was dissolved in 4 mL of 1:1HOAc/CHCl₃ and treated with NBS (44 mg, 0.25 mmol). After stirring for ½hour, the reaction was concentrated to dryness and treated with 2 mLeach of EtOH and 40% aqueous KOH. The mixture was heated to 100° C.overnight, cooled, and diluted with water. The product was extracted 2×into DCM (2×4 mL), concentrated, and purified by preparative HPLC-MS. ¹HNMR (CD₃OD) δ 7.19 (s, 1H), 3.40-3.34 (m, 2H), 3.28 (s, 2H), 3.21-3.17(m, 2H), 1.41 (s, 6H); MS: ESI (positive): 260, 262 (M+H).

Example 35(R,S)-2-Bromo-4-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme9)

a.)(E,Z)-4-Ethylidene-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

KHMDS (233 mg, 1.17 mmol) was added to a solution of(Ethyl)triphenylphosphonium bromide (466 mg, 1.26 mmol) in THF (5 mL)cooled to 0° C. and the resultant solution was stirred for 20 minutes.The product from Example 1, step c) (200 mg, 0.837 mmol) in THF (5 mL)was added to the reaction and the reaction was warmed to ambienttemperature over 1 hour. The reaction was quenched with water andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and the crude product was purified by silica gelchromatography (EtOAc/Hex-gradient) to give 151 mg of the subtitlecompound as a mixture of the E and Z isomers. MS: ESI (positive): 252(M+H).

b.) (R,S)-4-Ethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step a) (151 mg, 0.602 mmol) was stirred with 10% Pd/C(50 mg) in ethanol (3 mL) under H₂ (1 atm) for overnight. The reactionwas filtered over celite and concentrated to dryness to give the 131 mgof the subtitle compound as a purple oil that was used without furtherpurification. MS: ESI (positive): 254 (M+H).

c.)(R,S)-2-Bromo-4-ethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The subtitle compound was prepared by the method of Example 18, step d)using the product from step b) and was used in crude form withoutpurification.

d.) (R,S)-2-Bromo-4-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The title compound was prepared by the method described in Example 18,step e) using the product from example step c). ¹H NMR (CO₃OD) δ 6.88(s, 1H), 3.19-3.28 (m, 3H), 2.92-3.15 (m, 4H), 1.61-1.84 (m, 2H), 0.98(t, J=7.3 Hz, 3H). MS: ESI (positive): 260 (M+H).

Example 362-Bromo-3,4-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme9)

a.)3-Bromo-4-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of Example 23, step c) (enantiomer 2, 0.75 g, 1.9 mmol) andZn (0.25 g, 3.8 mmol) were heated to reflux in 20 mL each water andHOAc. After ½ hour, the reaction was cooled, diluted with EtOAc, andwashed 2× with water. The organic layer was dried over MgSO₄ andconcentrated to give 490 mg of the subtitle compound as an oil, whichwas used without further purification.

b.) 3,4-Dimethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step a) (150 mg, 0.47 mmol) was dissolved in 3 mL dioxaneand treated with Me₂Zn (0.47 mL of 2M in toluene) and Pd(ddf)₂Cl₂ (11mg, 0.014 mmol). After heating to 100° C. for 3 hours, the reaction wasquenched with water and filtered. The filtrate was partitioned betweenEtOAc and water (7 mL each). The organic layer was dried over MgSO4 andconcentrated to give 92 mg of the subtitle compound, which was usedwithout further purification.

c.)2-Bromo-3,4-dimethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step b) (92 mg, 0.36 mmol) was dissolved in 4 mL of 1:1HOAc/CHCl₃ and treated with NBS (67 mg, 0.38 mmol). After stirring for ½hour, the reaction was diluted with EtOAc (70 mL), washed with water(3×30 mL), and 1M NaOH (2×30 mL). The organic solution was dried overMgSO₄ and concentrated. The crude product was purified by silica gelchromatography (EtOAc/Hex-gradient) to give 90 mg of the subtitlecompound.

d.) 2-Bromo-3,4-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step c) was deprotected as described for Example 20, stepb). The title compound was obtained after purification by preparativeHPLC-MS. ¹H NMR (CD₃OD) δ 3.59-3.08 (m, 7H), 2.13 (s, 3H), 1.31 (d,J=7.2 Hz, 3H), MS: ESI (positive): 260, 262 (M+H).

*Enantiomer 1 can be prepared in a similar fashion.

Example 372-Bromo-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene(Scheme 10)

a.)(E,Z)-4-Ethoxycarbonylmethylene-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

To a solution of triethyl phosphonoacetate (4 mL, 16.74 mmol) inanhydrous THF (100 mL) was added a 1.6M LHMDS solution in THF (15 mL).The mixture was stirred at for 15 minutes followed by the addition ofproduct from Example 1, step c) (2.0 g, 8.37 mmol). The reaction wasstirred overnight then treated with additional LHMDS solution (3.2 mL of1.6 M) and triethylphosphonoacetate (800 μL, 3.3 mmol). After stirring 3hours, the reaction was quenched with water and diluted with DCM. Theorganic layer was dried over MgSO₄ and concentrated to give the subtitlecompound, which was used without further purification. MS: ESI(positive): 310 (M+H).

b.)(R,S)-4-Ethoxycarbonylmethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step a) (2.47 g, 8 mmol) was stirred with 2.0 g of 10%Pd/C (wet, Degussa grade E101) in methanol (8 mL) under H₂ (1 atm) for72 hours. The reaction was filtered over celite and concentrated todryness to give the subtitle compound as an oil, which was used withoutfurther purification. MS: ESI (positive): 312 (M+H).

c.)(R,S)-4-Carboxymethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

The product of step b) (2.47 g, 8 mmol) was stirred in ethanol (60 mL)with 1M NaOH (30 mL) at ambient temperature overnight. The reaction wasacidified with 1M HCl and partitioned between DCM and water. The organiclayer was washed with water, dried over MgSO₄, and concentrated todryness to give the 2.13 g of the subtitle compound as a yellow oil,which was used without further purification. MS: ESI (positive): 284(M+H).

d.)(R,S)-3-Oxo-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopenta[cd]azulene-6-carboxylicacid ethyl ester

Oxalyl chloride (3 mL, 37.7 mmol) and a catalytic amount of DMF wereadded to a solution of the product from step c) (2.13 g, 7.54 mmol) inDCM (40 mL) and the reaction was stirred at ambient temperature for 1hour. The reaction was concentrated to dryness and redissolved indichloroethane (100 mL). AlCl₃ (2.0 g, 15.1 mmol) was added to thesolution and the reaction was stirred at ambient temperature overnight.The reaction was quenched with ice and partitioned between DCM andwater. The organic layer was concentrated to give the subtitle compound,which was purified by silica gel chromatography (EtOAc/Hex-gradient,isolated 1.02 g) prior to use in subsequent steps. MS: ESI (positive):266 (M+H).

e.)(R,S)-3,4,4a,5,7,8-Hexahydro-1-thia-6-aza-cyclopenta[cd]azulene-6-carboxylicacid ethyl ester

AlCl₃ (627 mg, 4.72 mmol) was added to BH₃tBuNH₂ (492 mg, 5.66 mmol) inDCM (2 mL) at 0° C. The solution was stirred for 10 minutes then treatedwith the product from step d) (250 mg, 0.943 mmol) as a solution in DCM(1 mL). After warming to rt, the reaction was quenched with 0.1M HCldropwise and concentrated to dryness. The reaction was diluted in 1M HCland extracted into EtOAc. The organic layer was concentrated to give thesub-title compound, which was purified by silica gel chromatography(EtOAc/Hex-gradient) prior to use in subsequent steps. MS: ESI(positive): 252 (M+H).

f.)(R,S)-2-Bromo-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopenta[cd]azulene-6-carboxylicacid ethyl ester

The sub-title compound was prepared by the method of Example 18, step d)using the product from step e) and was used in crude form withoutpurification.

q.) 2-Bromo-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene

The title compound was prepared by the method described in Example 18,step e) using the product from step f) and purified by preparativeHPLC-MS. The two enantiomers were separated using a Chiralpak® AD-RH®20×250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase)to give enantiomer 1 (rt=8.6 minutes) and enantiomer 2 (rt=10.8 minutes)of the title compound. ¹H NMR (CD₃OD) δ 3.45-3.56 (m, 2H), 2.89-3.08 (m,3H), 2.45-2.65 (m, 4H), 1.99-2.04 (m, 2H). MS: ESI (positive): 260(M+H).

Example 38(R,S)-2-Methyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene:(Scheme 10)

a.)(R,S)-2-Methyl-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopenta[cd]azulene-6-carboxylicacid ethyl ester

A solution of 2M Me₂Zn in toluene (1.5 mL) was added to the product fromExample 37, step f) (50 mg, 0.150 mmol) and Pd(dppf)₂Cl₂ (4 mg, 0.0045mmol) in dioxane (1 mL). After heating to 100° C. for 3 hours, thereaction was quenched with water and extracted into ethyl acetate. Theorganic layers were combined and concentrated to give the subtitlecompound that was used in crude form without purification. MS: ESI(positive): 266 (M+H).

b.)(R,S)-2-Methyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene

The title compound was prepared by the method described in Example 18,step e) using the product from step a) and purified by preparativeHPLC-MS. ¹H NMR (CD₃OD) δ 3.52-3.64 (m, 2H), 3.25-3.30 (m, 1H),2.86-3.10 (m, 4H), 2.46-2.73 (m, 4H), 2.23 (s, 3H). MS: ESI (positive):194 (M+H).

Example 392-tert-Butyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene(Scheme 10)

a.)(R,S)-2-tert-Butyl-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopenta[cd]azulene-6-carboxylicacid ethyl ester

The product from Example 37, step e) (100 mg, 0.398 mmol), BF₃OEt (50μL, 0.398 mmol), and tert-butanol (56 μL, 0.597 mmol) were heated to 75°C. for 2 hours in dichloroethane (1 mL). The reaction was quenched withwater and extracted into DCM. The organic layers were combined andconcentrated overnight to give the subtitle compound that was used incrude form without purification. MS: ESI (positive): 308 (M+H).

b.)2-tert-Butyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene

The title compound was prepared by the method described in Example 18,step e) using the product from step a). The two enantiomers wereseparated using a Chiralpak® AD-RH® 20×250 mm column from ChiralTechnologies (10 mL/min MeOH mobile phase) to give enantiomer 1 (rt=7.7minutes) and enantiomer 2 (rt=10.2 minutes) of the title compound. ¹HNMR (CD₃OD) δ 3.20-3.34 (m, 2H), 2.91-3.01 (m, 1H), 2.56-2.91 (m, 5H),2.27-2.39 (m, 2H), 1.74-1.88 (m, 1H), 1.30 (s, 9H). MS: ESI (positive):236 (M+H).

Example 40 2-Trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 1a)

a.) 2-Iodo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

A solution of the product from Example 1, step d) (470 mg, 2.09 mmol) inCHCl₃ (5 ml) and AcOH (5 ml) was treated with N-iodosuccinimide (493 mg,2.19 mmol) at 22° C. After 1 hour, the reaction was diluted with CH₂Cl₂(20 ml) and poured into sat. NaHCO₃ (20 ml). The organic layer waswashed with brine (1×20 ml), dried (MgSO₄) and concentrated providingthe crude subtitle compound as a yellow oil, which was used withoutfurther purification.

b.)2-Trifluoromethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step a.) (75 mg, 0.21 mmol) in DMF (0.5ml) and NMP (0.5 ml) was treated with bipyridyl (43 mg, 0.27 mmol), CuI(44 mg, 0.23 mmol), KF (13 mg, 0.23 mmol) andtrimethylsilyltrifluoromethane (2.1 ml, 1.05 mmol). The reaction mixturewas heated to 80° C. for 3 days. The reaction was cooled and filteredthrough celite washing with EtOAc (20 ml). The eluent was washed withbrine (2×3 ml) and dried (MgSO₄) providing the subtitle compound as abrown oil that was used without further purification.

c.) 2-Trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

A solution of the crude product from step b.) (26 mg, 0.089 mmol) inCH₂Cl₂ (0.5 ml) was treated with iodotrimethylsilane (19 μl, 0.134 mmol)at 50° C. for 12 hours. The reaction was quenched by the addition ofMeOH and the solvent was evaporated. The residue was purified bypreparative LC/MS providing the title compound. NMR (300 MHz, CDCl₃) δ7.18 (s, 1H); 3.42-3.56 (m, 6H); 3.31-3.39 (m, 2H), 2.09 (s, 1H); MS:ESI (positive): 222 (M+H).

Example 413-Chloro-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 1b)

a.) 2,3-Dichloro-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from Example 4, step H) (323 mg, 1.25 mmol) inCH₂Cl₂ (6.25 ml) was cooled to 0° C. and triethylamine (522 μl, 3.75mmol) was added followed by ethylchloroformate (144 μl, 1.5 mmol). After1.5 hours the reaction was poured into water (25 ml) and diluted withEtOAc (50 ml). The organic layer was dried (MgSO₄) and concentratedproviding 341 mg (93%) of the subtitle compound that was used withoutfurther purification. MS: ESI (positive): 294, 296 (M+H).

b.) 3-Chloro-2-iodo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step a) (129 mg, 0.44 mmol) in anhydrousTHF (2.2 ml) was cooled to −78° C. and treated with 1.5 equiv of n-BuLi(412 μl, 0.66 mmol). After 1 h, the reaction was quenched with a THFsolution of I₂ (167 mg, 0.66 mmol). The reaction was warmed to 22° C.and diluted with EtOAc (15 ml). The organic layer was washed with sat.NaSO₃ (5 ml), brine (5 ml) and dried (MgSO₄) providing 98 mg (58%) ofthe crude subtitled compound that was used without further purification.MS: ESI (positive): 386 (M+H).

c.)3-Chloro-2-trifluoromethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step b) (140 mg, 0.363 mmol) in NMP (0.9ml) and DMF (0.9 ml) was treated with CuI (76 mg, 0.39 mmol), KF (46.4mg, 0.79 mmol), bipyridyl (74 mg, 0.472 mmol) and TMSCF₃ (267 μl, 1.81mmol). The mixture was heated to 80° C. for 12 hours. The crude reactionmixture was diluted with EtOAc and filtered through celite. The organicphase was washed with H₂O (2×1 ml), brine (1×1 ml), dried (MgSO₄) andconcentrated. The crude product was purified by preparative TLC using10:1 hexanes/EtOAc providing 14.4 mg (12.1%) of the subtitle compound.

d.)3-Chloro-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

A solution of the product from step c) (14.4 mg, 0.044 mmol) in CH₂Cl₂(220 μl) was treated with iodotrimethylsilane (19 μl, 0.13 mmol) at 60°C. for 12 hours. The reaction was quenched by the addition of MeOH andthe solvent was evaporated. The residue was purified by preparativeLC/MS providing 2.3 mg (18%) of the title compound. MS: ESI (positive):256 (M+H).

Example 423-Bromo-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 1b)

a.) 3-Bromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

A solution of the product from example 3, step a) (148 mg, 0.39 mmol) inAcOH (80 μl) and H₂O (1.92 ml) was treated with Zn (76 mg, 1.17 mmol) at105° C. for 4.5 hours. Next, the contents were cooled to 22° C., pouredinto sat. NaHCO₃ (25 ml) and extracted with EtOAc (2×25 ml). The organiclayer was dried (MgSO₄) and concentrated providing 80 mg (68%) of thesubtitle compound, which was used without further purification.

b.) 3-Bromo-2-iodo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step a) (124 mg, 0.41 mmol) in CHCl₃ (1.0ml) and AcOH (1.0 ml) was treated with N-iodosuccinimide (97 mg, 0.43mmol) for 30 minutes. Next, the crude reaction was poured into sat.NaHCO₃ (5 ml) and extracted with CH₂Cl₂ (2×4 ml). The organic layer waswashed with sat. NaHCO₃ (3 ml), dried (extrelut column), concentratedand purified by preparative TLC (80% hexanes:20% EtOAc) providing 134 mg(76%) of the subtitle compound.

c.)3-Bromo-2-trifluoromethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step b) (134 mg, 0.31 mmol) in NMP (1 ml)and DMF (1 ml) was treated with KF (20 mg, 0.34 mmol), CuI (65 mg, 0.34mmol) and bipyridyl (62 mg, 0.4 mmol) at 50° C. for 15 minutes. Next, a0.5 M solution of trimethylsilyltrifluoro-methane (3.1 ml, 1.55 mmol)was added and the reaction mixture was stirred 16 hours at 80° C. Thereaction mixture was cooled to 22° C., diluted with CH₂Cl₂ (5 ml) andwashed with brine (10 ml). The aqueous layer was extracted with CH₂Cl₂(3×5 ml) and the combined organic layers were dried (extrelut column),passed through a plug of silica gel, concentrated and purified bypreparative LC/MS providing 26 mg (23%) of the subtitle compound.

d.) 3-Bromo-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

A solution of the product from step c) (51 mg, 0.137 mmol) in CH₂Cl₂(685 μl) was treated with iodotrimethylsilane (59 μl) at 50° C. for 16hours. The reaction was quenched by the addition of MeOH and the solventwas evaporated. The residue was purified by preparative LC/MS providing16 mg (39%) of the title compound. NMR (300 MHz, CDCl₃) δ 4.10-4.40 (brs, 1H); 2.90-3.60 (m, 8H). MS: ESI (positive): 300, 302 (M+H).

Example 43 3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme3)

a.) 3-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

A solution of the product from Example 42, step a) (122 mg, 0.40 mmol)in dry THF (2 ml) was treated with NiCl₂(dppp) (2-3 mg, 0.004 mmol)followed by dropwise addition of a 1.4 M solution of methylmagnesiumbromide (0.71 ml, 1 mmol) at 22° C. and then the reaction was refluxedfor 16 hours. The reaction mixture was cooled to 22° C., diluted withether (5 ml), and quenched with 1N HCl (2 ml). The aqueous layer wasback extracted with ether (3×5 ml). The combined organic extracts werewashed with water (10 ml) and dried (MgSO₄). The solvent was evaporatedgiving the crude subtitle compound as a tan oil, which was used withoutfurther purification.

b.) 3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

A solution of the product from step a) in CH₂Cl₂ (1 ml) was treated withiodotrimethylsilane at 50° C. for 16 hours. The reaction was quenched bythe addition of MeOH and the solvent was evaporated. The residue waspurified by preparative LC/MS providing 1.6 mg of the title compound.NMR (300 MHz, CDCl₃) δ 6.69 (d, J=1 Hz, 1H); 4.8-5.2 (br s, 1H);3.20-3.40 (m, 6H); 3.00-3.1 (m, 2H); 2.14 (d, J=1 Hz, 3H); MS: ESI(positive): 168 (M+H).

Example 442-tert-Butyl-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 5)

a.)2-tert-Butyl-3-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

To a stirred solution of the product of Example 18, step a) (20 mg,0.078 mmol) in 0.5 mL DCE was added t-Butanol (25 uL, 0.26 mmol)followed by BF₃—OEt₂ (10 uL, 0.078 mmol). The reaction was heated to 75°C. for 2 hours. The reaction was allowed to cool to room temperature,concentrated to dryness, and the residue used without furtherpurification. MS: ESI (positive): 312 (M+H).

b.) 2-tert-Butyl-3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

The product of step a) was treated with 0.5 mL each of EtOH and 40%aqueous KOH. After heating to 100° C. for 18 hours, the reaction wascooled, diluted with water, and extracted into DCM (2×10 ml). Theorganic layer was concentrated to dryness and the residue purified bypreparative HPLC-MS to give the title compound. ¹H NMR (300 MHz, CD₃OD)δ 3.78 (s, 3H); 3.30-3.38 (m, 4H); 3.06-3.15 (m, 2H); 2.94-3.03 (m, 2H);1.45 (s, 9H). MS: ESI (positive): 240 (M+H).

Example 45 2-tert-Butyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine(Scheme 9)

To a stirred solution of the product from Example 1, step d) (66 mg,0.29 mmol) in 2.5 mL of DCE was added t-Butanol (36 uL, 0.38 mmol) andBF₃—OEt₂ (36 uL, 0.29 mmol). The reaction was heated to 60° C. for 2hours. The reaction was concentrated to dryness and treated with 2 mLeach of EtOH and 40% aqueous KOH. The mixture was heated to 100° C.overnight, cooled, and diluted with water. The product was extractedinto DCM (2×10 mL), concentrated, and purified by preparative HPLC-MS togive the title compound. MS: ESI (positive): 210 (M+H).

Example 462-tert-Butyl-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme4) Example 473-Chloro-2-(1,1,3,3-tetramethyl-butyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine(Scheme 4) Example 483-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme 4)

a.) 3-Chloro-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acidethyl ester

A solution of the product from Example 41 step a.) (382 mg, 1.3 mmol) inTHF (6.5 ml) was cooled to −78° C. and treated with a 1.6 M solution ofn-BuLi (2.26 ml, 1.36 mmol). After 1 hour, the reaction was quenchedwith water and extracted with EtOAc (2×30 ml). The organic layer waswashed with brine (1×15 ml), dried (MgSO₄) and concentrated. The crudeyellow oil was purified by silica gel chromatography(EtOAc/Hexane-gradient) providing 156 mg (46%) of the subtitle compound.¹H NMR (300 MHz, CDCl₃) δ 6.88 (s, 1H); 4.19 (q, J=7 Hz, 2H); 3.57-3.72(m, 4H); 2.92-3.03 (m, 2H); 2.81-2.92 (m, 2H); 1.29 (t, J=7 Hz, 3H).

b.)2-tert-Butyl-3-chloro-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylicacid ethyl ester

A solution of the product from step a.) (156 mg, 0.6 mmol) indichloroethane (3 ml) was treated with t-BuOH (172 μl, 1.8 mmol) andBF₃—OEt₂ (113 μl, 0.9 mmol). The reaction mixture was heated at 85° C.for 6 hours followed by evaporation of the solvent providing the crudesubtitle compound.

c.) 2-tert-Butyl-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine,Example 44;3-Chloro-2-(1,1,3,3-tetramethyl-butyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine,Example 45; 3-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine, Example46

A solution of the crude product from step b.) in EtOH (4 ml) and 40%aqueous KOH (4 ml) was treated with tetra-butylammonium bromide (20 mg)and heated to 95° C. for 2 days. Next, the reaction was cooled to 22° C.and extracted with CH₂Cl₂ (3×25 ml). The organic layer was washed withbrine (1×10 ml), dried (MgSO₄), and concentrated to dryness. The residuewas purified by preparative LC/MS providing the subtitle compounds. (A)¹H NMR (300 MHz, CDCl₃) δ 6.50-6.80 (br s, 1H); 3.05-3.14 (m, 4H);2.87-2.99 (m, 4H); 1.43 (s, 9H); MS: ESI (positive): 244 (M+H); (B) ¹HNMR (300 MHz, CDCl₃) δ 3.58-3.70 (br s, 1H); 2.98-3.09 (m, 4H);2.88-2.94 (m, 2H); 2.82-2.87 (m, 2H); 1.91 (s, 2H); 1.46 (s, 6H); 0.81(s, 9H); MS: ESI (positive): 300 (M+H); (C) ¹H NMR (300 MHz, CDCl₃) δ6.75 (s, 1H); 2.92-3.11 (m, 6H); 2.85-2.90 (m, 2H); 2.72-2.82 (br s,1H); MS: ESI (positive): 188 (M+H).

Example 49 2-Bromo-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine (Scheme 11)

a.) Furan-2-yl-oxo-acetic acid ethyl ester

Furan-2-yl-oxo-acetic acid (15 g, 107 mmol), dissolved in CHCl₃ (420ml), was treated with EtOH (9.6 ml, 165 mmol) and H₂SO₄ (1 ml) andheated to 63° C. for 12 hours. Next, the reaction mixture wastransferred to a separatory funnel and washed with sat. NaHCO₃ (100 ml).The organic layer was washed with brine (100 ml), dried (MgSO₄) andconcentrated providing 16.9 g (66%) of the above subtitle compound,which was carried forward without further purification.

b.) Furan-2-yl-hydroxy-acetic acid

A solution of the product from step a.) (25 g, 135 mmol) in EtOH (250ml) was cooled to 0° C. and treated with a solution of NaBH₄ (2.5 g, 66mmol) in H₂O (27 ml) for 5 minutes. Next, the reaction mixture wasquenched with AcOH (17 ml) and H₂O (271 ml) and concentrated to dryness.The crude oil was dissolved in CH₂Cl₂ (300 ml), washed with brine (2×100ml), dried (MgSO₄) and concentrated providing 17.5 g (70%) of the abovesubtitle compound, which was carried forward without furtherpurification.

c.) (3-Carboxymethyl-furan-2-yl)-acetic acid

A solution of the product from step b.) (10.9 g, 64 mmol) in decalin(193 ml) was treated with trimethylorthoacetate (48.2 ml, 384 mmol) andhexanoic acid (2.0 ml). Next, the reaction mixture was fitted with aVigreaux column and heated to 180° C. for 18 hours. Additional hexanoicacid (3×1.5 ml) aliquots of hexanoic acid were added every 2 hours forthe first 6 hours of reaction time. Next, the reaction was cooled to 22°C. and extracted with MeOH providing 27 g of a crude mixture of thediester and decalin. This mixture was dissolved in MeOH (250 ml), cooledto 0° C., and treated with 2 M NaOH (150 ml). After 12 hours, thesolvent was evaporated and the residue was taken up in 2 N NaOH (100 ml)and washed with ether (2×150 ml). The basic layer was acidified with 4 MHCl to pH 1 and back extracted with EtOAc (4×100 ml). The organic layerwas washed with brine, dried (MgSO₄) and concentrated providing 6.4 g(54%) of the above subtitle compound.

d.) 2-[3-(7-Hydroxy-ethyl)-furan-2-yl]-ethanol

A solution of the product from step c.) (6.4 g, 35 mmol) in dry THF (400ml) was cooled to 0° C. and a 1.0 M solution of BH₃ in THF (174 ml, 174mmol) was added dropwise over 10 minutes. After the addition wascomplete the mixture was stirred for an additional 20 minutes at 0° C.and then warmed to 22° C. for 2 hours. Next, the mixture was poured intoice cold sat. NaHCO₃ (300 ml) and extracted with EtOAc (2×200 ml). Theorganic layer was dried (MgSO₄) and concentrated providing 3.58 g (65%)of the subtitle compound. MS: ESI (positive): 157 (M+H).

e.) Methanesulfonic acid2-[3-(2-methanesulfonyloxy-ethyl)-furan-2-yl]-ethyl ester

A solution of the product from step d.) (3.58 g, 22.9 mmol) in CH₂Cl₂(114 ml), was cooled to 0° C., and treated with triethylamine (9.56 ml,68.7 mmol) followed by dropwise addition of methanesulfonyl chloride(3.88 ml, 50.4 mmol) over 10 minutes. After 1 hour, the reaction mixturewas transferred to a separatory funnel and extracted with ice water(1×50 ml), 10% citric acid (2×50 ml), sat. NaHCO₃ (2×50 ml) and brine(1×50 ml). The organic layer was dried (MgSO₄), concentrated to 20 ml,diluted with dry dioxane (42 ml) and further concentrated to removeremaining CH₂Cl₂. The resulting dioxane solution of the bismesylate wasimmediately carried into step f)

f.) 6-Benzyl-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine

The bismesylate dioxane solution, generated in step e), was diluted withdry dioxane (168 ml) and transferred to a 3-neck reaction flask equippedwith a dropping funnel and condenser. Anhydrous K₂CO₃ (46.5 g, 337 mmol)was added and the mixture was heated to 102° C. Next, a solution ofbenzylamine (7.5 g, 70.1 mmol) in dioxane (74.4 ml) was added dropwiseover 45 minutes and the reaction was refluxed for 18 hours. The mixturewas cooled to 22° C., the salts were filtered off, and the solvent wasevaporated. The crude oil was purified by silica gel chromatography(EtOAc/Hexane-gradient) providing 2.56 g (49%) (combined yield oversteps e and f) of the subtitle compound. MS: ESI (positive): 228 (M+H).

g.) 5,6,7,8-Tetrahydro-4H-furo[2,3-d]azepine Hydrochloride

A solution of the product from step f) (2.56 mg, 11.3 mmol) in anhydrousdichloroethane (56 ml) was cooled to 0° C., treated with 1-chloroethylchloroformate (6.11 ml, 56.4 mmol) and the reaction was warmed to 22° C.for 1 hour. The reaction was diluted with CH₂Cl₂ (100 ml) and washedwith sat. NaHCO₃ (50 ml). The sat. NaHCO₃ was back extracted with CH₂Cl₂and the combined organic layers were washed with brine (50 ml), dried(MgSO₄) and concentrated providing an oily residue, which was taken upin anhydrous MeOH (150 ml) and refluxed for 1 hour. The MeOH wasevaporated and the crude was triturated with ether and filteredproviding 1.71 g (87%) of the subtitle compound. ¹H NMR (300 MHz, DMSO)δ 9.56 (br s, 2H); 7.43 (d, J=2 Hz, 1H); 6.34 (d, J=2 Hz, 1H); 3.18-3.30(br m, 4H); 3.03-3.10 (br m, 2H); 2.74-2.82 (br m, 2H); MS: ESI(positive): 138 (M+H).

h.) 4,5,7,8-Tetrahydro-furo[2,3-d]azepine-6-carboxylic acid tert-butylester

A solution of the product from step g) (500 mg, 2.88 mmol) in acetone(7.2 ml) and water (7.2 ml) was treated with NaHCO₃ (484 mg, 5.76 mmol)and di-tert-butyl dicarbonate (691 mg, 3.17 mmol) under vigorousstirring for 1 hour. The contents were diluted with H₂O (10 ml) andextracted with EtOAc (2×50 ml). The organic layer was dried (MgSO₄),concentrated and purified by chromatography (EtOAc/Hexane-gradient)providing 643 mg (94%) of the subtitle compound. MS: ESI (positive): 238(M+H).

i.) 2-Bromo-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine

A solution of the product from step h) (50 mg, 0.21 mm(1) in CHCl₃ (527μl) and AcOH (527 μl) was treated with N-bromosuccinimide (38.1 mg, 0.21mmol) at 22° C. After 1 hour, the contents were poured into sat. NaHCO₃and extracted with EtOAc (2×5 ml). The organic layer was washed withbrine (1×5 ml), dried (MgSO₄) and purified by preparative TLC (80%hexanes:20% EtOAc) providing2-bromo-4,5,7,8-tetrahydro-furo[2,3-d]azepine-6-carboxylic acidtert-butyl ester which was directly treated with 4 M HCl in dioxane (2ml). The dioxane was evaporated and the residue was dissolved in MeOHand purified by preparative LC/MS providing 1.3 mg of the titlecompound. ¹H NMR (CDCl₃) 6.08 (s, 1H); 3.02-3.07 (m, 4H); 2.89-2.92 (m,2H); 2.57-2.70 (m, 3H); MS: ESI (positive): 216, 218 (M+H).

The following procedure was utilized to evaluate representativecompounds of the present invention as 5HT_(2c) receptor agonists. Theresults of this assay are set forth in Table 1.

Cell Culture

VNV Isoform: HEK 293 EBNA expressing the human 5HT2c receptor (Burns etal., NATURE 387:30308, 1997) were grown in DMEM containing 10% dialysedFBS, 9 μg/ml blasticidin at 37° C. in 5% CO₂ atmosphere.

Calcium Mobilization

HEK 293 EBNA cells expressing human 5HT2, receptor (2×10⁴/well) wereseeded in black 384-well collagen coated plates and incubated overnightat 37° C. in a 5% CO2/95% atmosphere. After removing medium, cells weretreated with HBSS buffer (137 mM NaCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mMHepes, pH 7.5, 2.1 mM MgCl₂, 0.3 mM CaCl₂, 0.02 mM MgSO₄, 3.0 mM NaHCO₃,and 0.64 mM KH₂PO₄) containing the Calcium3 dye (Molecular Device, CA),2.5 mM probenecid and 0.08% pluronic acid for 60 minutes according tomanufacture's instruction. Compounds were diluted in CsCl Ringers buffer(58.3 mM CsCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes, pH 7.5, 2.1 mMMgCl₂, 1.2 mM CaCl₂). 5HT was utilized as a positive control. Ligandinduced calcium release and consequent fluorescence was measured on aFluorometric Imaging Plate Reader (FLIPR, Molecular Device, CA).

Data Analysis

All data were analyzed by nonlinear least square curve fitting usingPrism 4.0 software. Agonist stimulation of calcium-induced fluorescencein FLIPR was fitted to sigmoidal dose response using equationY=Bottom+(Top-Bottom)/(1+10̂((LogEC50−X))), where X is the logarithm ofconcentration of compounds and Y is the fluorescent response.

TABLE 1 Example 5-HT2c EC50 Number Molecule (hVSV, □M)  1

<0.01  2

<0.1  3

<0.01  4

<0.01  5

<0.01  6

>10  7

>10  8

<10  9

>10 10

>10 11

>10 12

<10 13

<10 14

<1 15

<10 16

<0.01 17

<0.01 18

<0.01 19

<1 20

<0.01 21

<0.1 22

<0.01 23, Enantiomer 1 23, Enantiomer 2

<0.1 <0.1 24, Enantiomer 1 24, Enantiomer 2

<0.1 <0.1 25

<1 26

<0.01 27

<0.01 28

<0.01 29

<10 30

<1 31

<0.1 32, Enantiomer 1 32, Enantiomer 2

<10 <0.1 33

<1 34

<10 35

<0.1 36, Enantiomer 1 36, Enantiomer 2

>10 <1 37, Enantiomer 137, Enantiomer 2

<1 <0.1 38

<1 39, Enantiomer 1 39, Enantiomer 2

<0.1 <0.01 40

<0.01 41

<0.1 42

<0.01 43

<1 44

<0.01 45

<0.1 46

<0.1 47

<10 48

<10 49

<1

1. A compound of the formula

where X is S, O or NR₅; R₁ and R₂ are independently selected from thegroup consisting of H, halogen, C₁₋₈ alkyl, C₁₋₈ alkylaryl, C₁₋₈ alkylheteroaryl, C₂₋₈ alkenyl, perhalo alkyl, CN, OR₅, SR₅, N(R₅)₂, CON(R₅)₂,NR₅COR₅, NR₅CO₂R₅, SO₂N(R₅)₂, NR₅SO₂R₅, aryl and heteroaryl, whereinsaid aryl or heteroaryl can be optionally substituted with up to threesubstituents selected from alkyl, halogen and alkoxy; R₃ is selectedfrom the group consisting of H, C₁₋₈ alkyl, C₁₋₈ alkylaryl, C₁₋₈alkylheteroaryl, OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH, —COO—C₁₋₈ alkyl,—CON(R₅)₂, and aryl; R_(3a) is H or R₃ and R_(3a) taken together areCH₂CH₂— or R₂ and R₃ form a 5- or 6-member ring; R₄ is selected from thegroup consisting of H, C₁₋₈ alkyl, C₁₋₈ alkylaryl, C₁₋₈ alkylheteroaryl,OR₅, —CH₂—O—C₁₋₈ alkyl, —CH₂OH, —COO—C₁₋₈ alkyl, and —CON(R₅)₂; R_(4a)is H or R₄ and R_(4a) taken together are —CH₂CH₂—; R₅ is selected fromthe group consisting of H, C₁₋₈ alkyl, C₁₋₈ alkylaryl, C₁₋₈alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl; with the provisosthat at least one of R₁, R₂, R₃, R_(3a), R₄, and R_(4a) must be otherthan hydrogen; if R₃ is OH, then at least one of R₁, R₂, R₄, and R_(4a)must be other than hydrogen; and if X is O, then at least one of R₃,R_(3a), R₄, and R_(4a) must be other than hydrogen; or apharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising at least one compound of claim 1 and apharmaceutically acceptable carrier.